USP11 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 11
HGNC Gene Symbol
USP11
Identifiers
hgnc:12609 NCBIGene:8237 uniprot:P51784
Orthologs
mgi:2384312 rgd:1303052
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP11
Number of Papers
95 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP11using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP11 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP11 deubiquitinates TGFBR1. 9 / 9
| 8

reach
USP11 deubiquitylates ALK5.

reach
It has been revealed that the DUBs, UCH37, USP11, and USP15, de-ubiquitinate and stabilize TbetaRI.

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.

ubibrowser
Review

reach
XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In this study, we show that USP11 has no effect on TbetaRI stability in human lung fibroblast cells, though Al-Salihi et al. 21 showed that USP11 de-ubiquitinates TbetaRI.

reach
USP11 augments TGFbeta signalling by deubiquitylating ALK5.

reach
USP11 was able to reduce ALK5 polyubiquitylation, although not to basal levels.

reach
For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].

reach
Over-expressed wt USP11 was able to deubiquitylate ALK5.
USP11 deubiquitinates PML. 8 / 8
| 1 6

ubibrowser
Review

reach
USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3) and Roc1 complex.

reach
Remarkably, USP11 was able to antagonize RNF4- and Roc1-Cul3-KLHL20-mediated PML ubiquitination in 293T cells and GBM cell line U87 (XREF_SUPPLEMENTARY).

reach
Next, we determined whether USP11 could deubiquitinate PML in vitro.

trips
USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3)-Roc1 complex.

reach
USP11 deubiquitinates PML.

reach
We demonstrated that USP11 deubiquitinates and stabilizes PML.

reach
By contrast, USP11 promotes deubiquitination and stabilization of PML [XREF_BIBR].
USP11 deubiquitinates SPRTN. 8 / 8
| 8

reach
To show that deubiquitination of SPRTN by USP11 is direct, we purified SFB-SPRTN, Myc-USP11, and Myc-USP11 C318S proteins from HEK 293T cells and performed an invitro DUB reaction by incubating SFB-SPRTN alone or with Myc-USP11 or Myc-USP11 C318S purified proteins.

reach
We observed that USP11, but not USP11 C318S catalytic mutant, deubiquitinated SPRTN (XREF_FIG E, anti-Ub blot) and reduced SPRTN auto-cleavage products (XREF_FIG E, IP blot).

reach
Upon formaldehyde treatment and other yet to be identified signals, SPRTN is deubiquitinated by USP11 (this study), USP7, and VCPIP1.

reach
Neither VCPIP1 nor USP11 induce SPRTN deubiquitylation when overexpressed, while USP7 does (XREF_SUPPLEMENTARY).

reach
USP11 mediates repair of DNA protein cross-links by deubiquitinating SPRTN metalloprotease.

reach
USP11 deubiquitinates SPRTN in cells and invitro.

reach
However, we observe that lack of SPRTN deubiquitination by USP11 and VCPIP1 did not affect recruitment on chromatin.

reach
USP11 deubiquitinates SPRTN upon DPC induction.
USP11 deubiquitinates NFKBIA. 7 / 7
| 6

reach
Once it is ubiquitinated, IkappaBalpha can be deubiquitinated by its associated USP11 in collaboration with USP15 to prevent excessive NF-kappaB activation induced by TNFalpha.

reach
In this assay, we found that USP11-WT but not -C318A mutant abrogated ubiquitination of Flag-IkappaBalpha (XREF_FIG).

reach
In this assay, we found that only USP11 full-length wild type abrogated ubiquitination of Flag-IkappaBalpha (XREF_FIG).

reach
However, we found that overexpression of USP11 C318A mutant only partially rescued the inhibitory effect of USP11-WT on TNFalpha induced IkappaBalpha ubiquitination (XREF_SUPPLEMENTARY) as well as TNFalpha- and IKKbeta induced NF-kappaB activation (XREF_SUPPLEMENTARY).

ubibrowser
Moreover, knockdown of USP11 expression enhances TNFalpha-induced IkappaBalpha ubiquitination and NF-kappaB activation.

reach
Subsequently we analyzed the effect of USP11 knockdown on the TNFalpha induced IkappaBalpha ubiquitination and NF-kappaB activation.

reach
These results demonstrate that USP11 deubiquitinates IkappaBalpha.
USP11 deubiquitinates PALB2. 6 / 6
| 5

reach
If USP11 antagonizes PALB2 ubiquitylation by CRL3-KEAP1, then removal of KEAP1 (or CUL3) should reverse the phenotypes imparted by loss of USP11.

ubibrowser
PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11

reach
These mechanisms might be of therapeutic importance in cancer, because defective HR renders cells susceptible to inhibition of base excision repair (BER) mediated by poly (ADP-ribose) polymerase 1 (PARP1) XREF_BIBR - XREF_BIBR : the deubiquitylating enzyme (DUB) ubiquitin carboxyl-terminal hydrolase 11 (USP11) deubiquitylates partner and localizer of BRCA2 (PALB2) during S and G2 phases following DNA damage, allowing the formation of the BRCA1, PALB2, and BRCA2 complex and HR repair to advance in these phases of the cell cycle 64.

reach
USP11 (Ubiquitin specific peptidase 11) deubiquitinates PALB2 ubiquitination to promote HR repair.

reach
Since recombinant USP11 can de-ubiquitylate PALB2 (1-103) in vitro (XREF_FIG), these results suggest that USP11 promotes the assembly of the BRCA1, PALB2, and BRCA2 complex by reversing the inhibitory ubiquitylation on the PALB2 Lys20/25/30 residues.

reach
USP11 deubiquitinates PALB2 and promotes BRCA1, PALB2, and BRCA2 complex formation.
USP11 deubiquitinates BRCA2. 6 / 6
| 5

reach
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability: USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C(MMC) regulates the stability of BRCA2 in a USP11-dependent manner [117].

reach
USP11 was shown to interact with and deubiquitinates BRCA2 and as well counteracts RNF4 induced SUMO-ubiquitin hybrid chains, suggesting the pleiotropic roles at DSBs sites [XREF_BIBR].

reach
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability : USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C (MMC) regulates the stability of BRCA2 in a USP11 dependent manner [XREF_BIBR].

reach
Although when overexpressed USP11 can deubiquitinate BRCA2 in vivo, it does not antagonize the MMC-induced ubiquitination and degradation of BRCA2 [185].
| PMC

ubibrowser
Review

reach
While BRCA2 could be deubiquitinated by USP11 in transient overexpression assays, a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels.
USP11 deubiquitinates TGFBR2. 5 / 5
| 4

reach
We demonstrate that knockdown of USP11 increases the ubiquitination of TbetaRII, whereas overexpression of USP11 greatly decreases ubiquitination of TbetaRII.

ubibrowser
Together, these data suggest that deubiquitination of TGFBR2 by USP11 effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis.

reach
The novel finding in this study is that USP11 de-ubiquitinates and stabilizes TbetaRII.

reach
USP11 de-ubiquitinates and stabilizes TbetaRII.

reach
Together, these data suggest that deubiquitination of TGFBR2 by USP11 effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis.
USP11 deubiquitinates NONO. 4 / 4
| 4

reach
Conversely, USP11 silencing with two independent shRNAs increased endogenous NONO poly-ubiquitination in A375 and SK-Mel28.

reach
Overexpression of WT-USP11, but not mutant USP11, reduced NONO ubiquitination.

reach
30 Here, we further revealed that NONO ubiquitination could be reversed by USP11 to avoid its degradation through the ubiquitin-proteasome pathway.

reach
3.4 USP11 deubiquitinates NONO.
USP11 deubiquitinates TP53. 4 / 4
| 1 2

reach
Similarly, it was found that USP11 deubiquitylates p53 in response to genotoxicity induced by etoposide.

reach
OTUD1, OTUD5 and USP11 directly deubiquitinating p53 and functional proteins were required for p53 stabilization [XREF_BIBR - XREF_BIBR].

trips
USP11 regulates p53 stability by deubiquitinating p53.

ubibrowser
Review
USP11 deubiquitinates LPAR1. 4 / 4
| 3

reach
Taken together, USP11 deubiquitinates and stabilizes LPA1, and LPA induced switching LPA1 association with USP11 to Nedd4L plays a critical role in LPA1 ubiquitination and degradation (XREF_FIG e).

reach
The stability of LPA1 is up-regulated by ubiquitin specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1 mediated pro inflammatory effects.

reach
3.4 Deubiquitination of LPA1 by USP11 Increases its Stability.

ubibrowser
The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects.
USP11 deubiquitinates Nucleoproteins. 3 / 3
| 3

reach
The result showed that both USP10 and USP11 specifically co-precipitated with NP-HA (lanes 1, 3 and 4, lower panel), consistent with the published result, and NP could be deubiquitinated by only USP11 but not USP10 (lanes 3 and 4, upper panel).

reach
(B) Deubiquitination of NP by cellular USP11 may lower its binding affinity to cRNA.

reach
These results combined suggest that USP11 inhibits viral RNA replication through deubiquitinating NP.
USP11 deubiquitinates RAE1. 3 / 3
| 2

reach
USP11 deubiquitinates RAE1 and plays a key role in bipolar spindle formation.

reach
We show here that deubiquitination of RAE1 by USP11 does not regulate RAE1 protein levels nor the SAC.

ubibrowser
USP11 deubiquitinates RAE1 and plays a key role in bipolar spindle formation.
USP11 deubiquitinates mgl-1. 3 / 3
| 3

reach
USP11 deubiquitinates and stabilizes Mgl-1 protein.

reach
Endogenous depletion of RanBPM inhibited the stabilizing action of USP11 on Mgl-1, indicating the crucial role of RanBPM in controlling the deubiquitination of Mgl-1 by USP11.

reach
With the presence of RanBPM, USP11 deubiquitinates Mgl-1 to stabilize, indicating that RanBPM is essential for Mgl-1 stabilization.
USP11 deubiquitinates XPC. 3 / 3
| 2

reach
Regulation of XPC deubiquitination by USP11 in repair of UV induced DNA damage.

reach
USP11 knockdown in HaCaT cells increased ubiquitination of XPC as compared to control cells, suggesting that USP11 is important in maintaining NER capacity, as USP11 mediates XPC deubiquitination at the chromatin following UVB damage [XREF_BIBR].

ubibrowser
Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage
USP11 deubiquitinates XIAP. 3 / 3
| 2

reach
Our identification of deubiquitylation of XIAP by USP11 adds up a novel layer for XIAP regulation.

reach
3.5 Identification of Molecular Motifs on USP11 and XIAP that Mediate Deubiquitylation of XIAP by USP11.

ubibrowser
Review
USP11 deubiquitinates H2AX. 3 / 3
| 2

reach
USP11 also functions in DSB repair, wherein USP11 deubiquitinates H2AX to regulate the recruitment of RAD51 and 53BP1 to damage foci.

ubibrowser
Review

reach
USP11 deubiquitinates H2AX, opposing the ubiquitinating activity of the RNF8 and RNF168 complex.
USP11 deubiquitinates PRC1. 3 / 3
| 2

ubibrowser
Review

reach
In some cancer types, PRC1 can be deubiquitinated by USP7, USP11 and USP26 [XREF_BIBR, XREF_BIBR].

reach
Lastly, USP7 and USP11 deubiquitinate PRC1, a protein found to contribute to cancer stemness [XREF_BIBR - XREF_BIBR].
USP11 deubiquitinates CDKN1A. 2 / 2
| 2

reach
As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCF SKP2, CRL4 CDT2, and APC/C CDC20 in a cell-cycle-independent manner.

reach
Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses.
USP11 deubiquitinates PCGF2. 2 / 2
| 2

reach
Importantly, over-expression of HA tagged USP7 or USP11 reduced the overall ubiquitination of MEL18 (XREF_FIG, lanes 2 and 4).

reach
Nevertheless, MEL18 and BMI were deubiquitylated by USP7 and USP11, two chromatin bound components of polycomb and repressive complex 1 complex components that influence the transcriptional regulation of p16INK4a [XREF_BIBR].
USP11 deubiquitinates TGFB. 2 / 2
| 2

reach
USP11 interacts with and deubiquitylates the type I TGFbeta receptor (ALK5), resulting in enhanced TGFbeta induced gene transcription.

reach
For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].
Modified USP11 leads to the deubiquitination of PML. 2 / 2
| 2

reach
In the reciprocal experiment, overexpression of USP11, but not its catalytically inactive mutant, reduced PML ubiquitination (XREF_FIG).

reach
Importantly, the NIC induced PML ubiquitination was abrogated by Hey1 depletion or USP11 overexpression (XREF_FIG).
USP11 deubiquitinates USP11. 2 / 2
| 2

reach
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability: USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C(MMC) regulates the stability of BRCA2 in a USP11-dependent manner [117].

reach
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability : USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C (MMC) regulates the stability of BRCA2 in a USP11 dependent manner [XREF_BIBR].
USP11 leads to the deubiquitination of SNAI1. 2 / 2
| 2

reach
Our results revealed that USP11 promoted EMT in ovarian cancer by deubiquitinating Snail, and USP11 may be a novel therapeutic target for ovarian cancer treatment.

reach
Upregulation of USP11 promotes epithelial-to-mesenchymal transition by deubiquitinating Snail in ovarian cancer.
Modified USP11 leads to the deubiquitination of TGFBR2. 2 / 2
| 2

reach
We demonstrate that knockdown of USP11 increases the ubiquitination of TbetaRII, whereas overexpression of USP11 greatly decreases ubiquitination of TbetaRII.

reach
Overexpression of USP11 reduces TbetaRII ubiquitination and increases TbetaRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA.
USP11 deubiquitinates IKBKB. 1 / 1
|

ubibrowser
Both USP11 and USP15 also negatively regulate and function by deubiquitinating IκB to sequester NFκB in the cytoplasm.
USP11 deubiquitinates Histone_H2B on K120. 1 / 1
| 1

reach
Although the function of USP11 in DSB repair will be discussed below, recently it is reported that USP11 directly and specifically deubiquitylates gammaH2AX, but not H2A (K119) and H2B (K120) in vitro[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP11 deubiquitinates CYLD. 1 / 1
| 1

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
USP11 deubiquitinates E7. 1 / 1
| 1

reach
USP-11 deubiquitylates specific substrates which play key roles in correct microtubule nucleation (RanBPM) [XREF_BIBR]; antigen presenting cell function (RELB) [XREF_BIBR]; inflammation, immunity, cell proliferation and apoptosis (TNFa induced NK-kB, and IKKa and p53 signaling pathway) [XREF_BIBR, XREF_BIBR]; and E7 modulated cell growth and transformation (HPV-16E7) [XREF_BIBR].
USP11 deubiquitinates USP9X. 1 / 1
| 1

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
USP11 deubiquitinates HDAC2. 1 / 1
| 1

reach
In contrast, USP11 failed to deubiquitinate HDAC2 (XREF_FIG).
USP11 deubiquitinates RANBP9. 1 / 1
|

ubibrowser
Review
USP11 deubiquitinates PTEN. 1 / 1
| 1

reach
Mechanistically, USP11 deubiquitinates PTEN to increase its stability, which promotes the inhibition of PI3K signalling 50.
USP11 deubiquitinates PPP1CA. 1 / 1
|

ubibrowser
Mechanically, USP11 stabilized PPP1CA by deubiquitinating and protecting it from proteasome-mediated degradation.
USP11 deubiquitinates ubiquitinated SPRTN. 1 / 1
| 1

reach
We observed that monoubiquitinated SPRTN is deubiquitinated by USP11 FL, but not C318S deubiquitinase inactive mutant (XREF_FIG C and Fig.S2A).
USP11 leads to the deubiquitination of NFkappaB. 1 / 1
| 1

reach
Subsequently we analyzed the effect of USP11 knockdown on the TNFalpha induced IkappaBalpha ubiquitination and NF-kappaB activation.
USP11 deubiquitinates USP15. 1 / 1
| 1

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
USP11 deubiquitinates EIF4B on aspartic acid. 1 / 1
| 1

reach
Remarkably, assessing deubiquitination levels of eIF4B in cell based assays we found that USP11 (wt and Asp mutant) was able to deubiquitinate eIF4B compared with GFP transfected cells, which did not occur for USP11 S453A.
USP11 deubiquitinates BECN1. 1 / 1
| 1

reach
USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1.
USP11 deubiquitinates CHUK. 1 / 1
|

ubibrowser
Review
USP11 deubiquitinates BMI1. 1 / 1
|

ubibrowser
Review
USP11 deubiquitinates EIF4B. 1 / 1
| 1

reach
Next, to demonstrate whether USP11 can directly deubiquitinate eIF4B, we performed in vitro deubiquitinase assays.
Modified USP11 leads to the deubiquitination of NFkappaB. 1 / 1
| 1

reach
Furthermore, knockdown of USP11 expression enhanced TNFalpha mediated IkappaBalpha ubiquitination and NF-kappaB activation but had no effect on TNFalpha mediated MAPK activation.
Modified USP11 leads to the deubiquitination of mgl-1. 1 / 1
| 1

reach
The result showed that dose dependent expression of USP11 gradually decreased the level of Mgl-1 ubiquitination.
USP11 deubiquitinates ILF3. 1 / 1
| 1

reach
Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis.
USP11 deubiquitinates E2F1. 1 / 1
|

ubibrowser
Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene expression and activate lung epithelial cells
USP11 deubiquitinates SMAD7. 1 / 1
| 1

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
USP11 leads to the deubiquitination of RNF4. 1 / 1
| 1

reach
Remarkably, USP11 was able to antagonize RNF4- and Roc1-Cul3-KLHL20-mediated PML ubiquitination in 293T cells and GBM cell line U87 (XREF_SUPPLEMENTARY).
USP11 deubiquitinates VGLL4. 1 / 1
|

ubibrowser
In this study, we identify deubiquitinating enzyme USP11 as a novel VGLL4 interactor.
USP11-R241Q leads to the deubiquitination of SOX11. 1 / 1
| 1

reach
Accordingly, the Usp11 R241Q mutant failed to reduce Sox11 ubiquitination level when overexpressed in cells (XREF_FIG).
USP11 deubiquitinates SMAD4. 1 / 1
| 1

reach
UCHL37, USP11, and USP15 de-ubiquitinate TbetaRI, XREF_BIBR, XREF_BIBR, XREF_BIBR while USP15, CYLD, and USP9X target SMAD4 or SMAD7.
Modified USP11 leads to the deubiquitination of NFKBIA. 1 / 1
| 1

reach
Overexpression of USP11 inhibits IkappaBalpha ubiquitination.
USP11 deubiquitinates NFE2L2. 1 / 1
| 1

reach
We further found that USP11 deubiquitinates NRF2; this modification stabilizes NRF2.
USP11-C318S deubiquitinates SPRTN. 1 / 1
| 1

reach
We observed that USP11, but not USP11 C318S catalytic mutant, deubiquitinated SPRTN (XREF_FIG E, anti-Ub blot) and reduced SPRTN auto-cleavage products (XREF_FIG E, IP blot).
USP11 deubiquitinates SOX11. 1 / 1
| 1

reach
Mechanistically, we show that Usp11 deubiquitinates Sox11, which is critical for Sox11 stabilization during cortical development.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP11 affects TGFB
| 2 14
USP11 activates TGFB. 10 / 19
| 2 14

reach
USP11, a ubiquitous protein in various human cells, has been shown to enhance TGFbeta receptor (ALK5) stability and regulate DNA repair.

eidos
Ubiquitin-specific peptidase 11 ( USP11 ) has been reported to promote transforming growth factor beta ( TGFbeta ) signaling which plays essential role underlying RIPF .

reach
While wild-type (wt) USP11 significantly enhanced TGFbeta induced transcriptional reporter activity, the catalytically inactive mutant USP11 (C318S) had no effect (see XREF_FIG d and the electronic supplementary material, figure S3).

reach
This result indicates a central role for the proteasome in USP11 modulation of TGFbeta pathway signalling.

reach
Ubiquitin-specific peptidase 11 (USP11) has been reported to promote transforming growth factor β (TGFβ) signaling which plays essential role underlying RIPF.

reach
Despite its interaction with SMAD7, we found that USP11 enhanced TGFbeta signalling and bound the TGFbeta R1 receptor (ALK5).

reach
USP11 overexpression in T EFF cells enhanced the activation of the TGF-beta pathway and promoted T REG or T H 17, but not Th1, cell differentiation in vitro and in vivo, an effect abrogated by USP11 gene silencing or the inhibition of enzymatic activity.

reach
USP11 knockdown inhibits TGFbeta pathway signalling.

reach
The DUBs USP4, USP11, USP15, and UCH37 have previously been demonstrated to modulate TGF-beta pathway activity by directly deubiquitinating the TbetaRI, resulting in increased TbetaRI stability (XREF_FIG) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.

reach
The deubiquitylase activity of USP11 is required to enhance TGFbeta induced gene transcription.

reach
11 In congruence with this, our results indicate that USP11 acts as an oncogene, because USP11 overexpression promotes the proliferation of melanoma cells, whereas knockdown of USP11 exhibits the opposite function.

reach
We also demonstrated that USP11 promoted the melanoma cells proliferation and tumorigenesis via NONO.

reach
3.5 USP11 promotes melanoma cell proliferation via NONO.

reach
Furthermore, we demonstrate that USP11 mediates the proliferation of melanoma cells via NONO because the effect of USP11 knockdown on melanoma cells could be rescued by introducing NONO.

reach
For example, the aberrant expression of USP11 was found to interact with nuclear factor 90 and promote its deubiquitination, to promote the proliferation and metastasis of hepatocellular carcinoma.

reach
Additionally, USP11 could promote cell proliferation and metastasis via regulating nuclear factor 90 (NF90) in hepatocellular carcinoma [XREF_BIBR].

reach
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.

reach
In congruence with previous report, 11 USP11 knockdown inhibited the proliferation of A375, which could be reversed by the introduction of ectopic NONO.

reach
Functionally, USP11 mediated melanoma cell proliferation via the regulation of NONO levels because ablation of USP11 inhibits the proliferation which could be rescued by ectopic expression of NONO protein.

reach
Namely, USP11 has been shown to promote the proliferation and metastasis of hepatocellular carcinoma (HCC), but the underlying molecular basis is poorly understood.

reach
USP11 depletion decreases DLBCL cell proliferation.

reach
Ablation of USP11 or RAE1 reduces cell proliferation of U2OS cells.

reach
Our observation that depletion of USP11 or inhibition using a non specific inhibitor such as Mitoxantrone significantly reduces DLBCL proliferation further supports the need for the development of USP11 specific inhibitors for targeting DLBCL.

reach
Functionally, USP11 mediated melanoma cell proliferation via the regulation of NONO levels because ablation of USP11 inhibits the proliferation which could be rescued by ectopic expression of NONO protein.

reach
Physiologically, USP11 depletion suppresses cell proliferation and wound healing in lung epithelial cells, and these effects are reversed by E2F1 and PEG10 overexpression.

reach
Functionally, USP11 mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo.
USP11 affects autophagy
| 4 14
USP11 activates autophagy.
| 4 9
| 4 9

reach
A series of in vitro and in vivo experiments revealed that USP11 promoted autophagy through AMPK/Akt/mTOR pathway via stabilizing valosin containing protein (VCP).

reach
In our study, we found that USP11 could induce resistance to chemotherapy by activating autophagy.

eidos
Collectively , these findings suggest that USP11 could promote autophagy via AMPK / Akt / mTOR signaling pathway dependent on VCP .

reach
The above experimental results have confirmed that USP11 could not only mediate the resistance to 5-Fu, but also induce autophagy in colorectal cancer cells.

eidos
USP11 promotes autophagy through AMPK / Akt / mTOR signaling pathway in a VCP-dependent manner Our previous experiments have confirmed that USP11 can promote autophagy in colorectal cancer cells , however , the underlying mechanisms were still unknown .

reach
Taken together these data, we hypothesized that USP11 might mediate resistance to 5-Fu by inducing autophagy in colorectal cancer cells and verified the hypothesis in follow-up experiments.

reach
Our study investigated the role of ubiquitin specific protease 11 (USP11) in CRC chemotherapy and found that USP11 could induce resistance to 5-fluorouracil by activating autophagy.

reach
Thus, we hypothesized that USP11 could promote resistance to 5-Fu in colorectal cancer by inducing autophagy.

reach
USP11 promotes autophagy through AMPK/Akt/mTOR signaling pathway in a VCP dependent manner.

reach
In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.
USP11 inhibits autophagy.
| 5
| 5

reach
Here, we show that the deubiquitinase USP11 restricts autophagy and that knockout (KO) of USP11 in mammalian cells results in elevated autophagic flux.

reach
Moreover, E2F1 and USP11 inhibited autophagy by regulating ERK and mTOR pathway.

reach
We also demonstrate that depletion of the USP11 homolog H34C03.2 in Caenorhabditis elegans triggers hyperactivation of autophagy and protects the animals against human β-amyloid peptide 42 aggregation-induced paralysis.

reach
The E2F1 and USP11 positive feedback loop promotes hepatocellular carcinoma metastasis and inhibits autophagy by activating ERK and mTOR pathway.

reach
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.
HEY1 affects USP11
| 13
HEY1 inhibits USP11.
| 8
HEY1 inhibits USP11. 8 / 8
| 8

reach
Importantly, Hey1 induced repression of USP11 was abrogated partially by mutating either of the first two Sp1 sites and completely by disrupting both (XREF_FIG), suggesting that Hey1 acts through Sp1 binding sites to repress USP11.

reach
Using luciferase reporter assay, we found that Hey1 repressed the USP11 promoter activity and that the +171/+335 (0.16 K) region of USP11 promoter was responsible for this repression (XREF_FIG).

reach
Overexpression of Hey1 in GBM cell lines U87 decreased USP11 mRNA and protein (XREF_FIG).

reach
Hey1 represses USP11 to downregulate PML.

reach
Thus, Hey1 functions as a transcriptional corepressor in USP11 transcription regulation and a complex crosstalk among transcriptional factors, histone modifiers and DNA methylation is involved in Hey1 mediated repression of USP11.

reach
In the reciprocal experiments, Hey1 knockdown in U87 and U251 cells upregulated USP11 mRNA, USP11 protein and PML protein, but not PML mRNA (XREF_FIG).

reach
We further showed that USP11 is transcriptionally repressed by the Notch effector Hey1.

reach
We have elucidated the mechanism by which Hey1 represses USP11 promoter activity (XREF_FIG).
HEY1 activates USP11.
| 3
HEY1 activates USP11. 3 / 3
| 3

reach
Consistent with the regulation of PML protein stability by USP11, Hey1 induced USP11 downregulation resulted in a concomitant reduction of PML protein but not mRNA.

reach
These findings support the idea that Hey1 induced USP11 and PML downregulation mediates the chemoresistant effect of Notch.

reach
To explore the mechanism of Hey1 induced USP11 downregulation, we analysed the 5 '-regulatory region of USP11 (XREF_FIG).
HEY1 decreases the amount of USP11.
| 2
HEY1 decreases the amount of USP11. 2 / 2
| 2

reach
However, it was recently demonstrated that Notch and Hey1 transcriptionally represses the expression of the PML deubiquitinase USP11, thereby down-regulating PML protein levels.

reach
We show that Notch acts through Hey1 to repress the expression of USP11, a deubiquitinating (DUB) enzyme for PML.
USP11 affects TGFB1
| 1 5
USP11 activates TGFB1.
| 5
USP11 activates TGFB1. 5 / 10
| 5

reach
Three examples of deubiquitinating enzymes for TbetaR-I are ubiquitin specific peptidase-4 (USP4), -11 (USP11) and -15 (USP15), all of which antagonize the effect of SMAD7 and strongly induce TGF-beta1 signalling [XREF_BIBR].

reach
As USP11 promotes TGFbeta-1 signaling through stabilization of TbetaRII, we hypothesize that USP11 may have a critical role in the development of lung fibrosis.

reach
De-ubiquitinating enzyme, USP11, promotes transforming growth factor beta-1 signaling through stabilization of transforming growth factor beta receptor II.

reach
Consistent with their findings, we also revealed that USP11 promotes TGFbeta-1 signaling.

reach
Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGFbeta-1 signaling through de-ubiquitination and stabilization of TbetaRII.
USP11 inhibits TGFB1.
| 1
USP11 inhibits TGFB1. 1 / 1
| 1

eidos
We verified that USP11 deficiency remarkably reinforced tight junction in the endothelial cells and alleviated TGF-beta1 to inhibit fibrosis of fibroblast cells .
USP11 affects LPAR1
| 3
USP11 activates LPAR1.
| 1
USP11 activates LPAR1. 1 / 8
| 1

reach
Here we report that a deubiquitinating enzyme, USP11, promotes LPA1 stability by reduction of LPA1 ubiquitination, resulting in enhanced LPA-LPA1 signal pathway.
USP11 inhibits LPAR1.
| 1
USP11 inhibits LPAR1. 1 / 2
| 1

reach
3.7 USP11 Inhibitor, Mitoxathrone, Reduces LPA1 Stability and Protects LPS Induced Lung Injury.
USP11 increases the amount of LPAR1.
| 1
USP11 increases the amount of LPAR1. 1 / 1
| 1

reach
Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS induced inflammatory responses and lung injury in preclinical murine models.
USP11 affects SOX11
| 11
USP11 activates SOX11.
| 6
USP11 activates SOX11. 5 / 5
| 5

reach
This Sox11 down-regulation was rescued by re-expression of wild-type Usp11, but not Usp11 R241Q (XREF_FIG).

reach
Whereas expression of wild-type Usp11 increased Sox11 abundance, this mutant did not up-regulate Sox11 (XREF_FIG).

reach
In summary, our study identifies the functions of Usp11 mediated Sox11 stabilization in cortical development, provides an explanation for the association of Usp11 mutation with neurological disorder, and highlights the importance of deubiquitination triggered protein stabilization in the developmental process.

reach
It is intriguing that Usp11 targets Sox11, but not its paralog Sox4, in the developing cortex.

reach
Last, using a cycloheximide-chase assay, we found that Usp11 knockdown decreased the stability of Sox11 (XREF_FIG).
USP11-R241Q activates SOX11. 1 / 1
| 1

reach
This Sox11 down-regulation was rescued by re-expression of wild-type Usp11, but not Usp11 R241Q (XREF_FIG).
USP11 increases the amount of SOX11.
| 2
USP11 increases the amount of SOX11. 2 / 2
| 2

reach
Human USP11 also up-regulated SOX11 expression, demonstrating the evolutional conservation of the Usp11 and Sox11 axis.

reach
As expected, Usp11 knockdown decreased the expression of Sox11.
USP11 decreases the amount of SOX11.
| 2
USP11-R241Q decreases the amount of SOX11. 1 / 1
| 1

reach
Accordingly, the Usp11 R241Q mutant failed to reduce Sox11 ubiquitination level when overexpressed in cells (XREF_FIG).
USP11 decreases the amount of SOX11. 1 / 1
| 1

reach
Knockdown of Usp11 in N2a cells using three independent short hairpin mediated RNAs (shRNAs) markedly reduced Sox11 protein level without affecting its mRNA level (XREF_FIG and fig.
USP11 inhibits SOX11.
| 1
USP11 inhibits SOX11. 1 / 1
| 1

reach
Using an antibody specific for K48 linked ubiquitin chains, we confirmed that Usp11 expression reduced Sox11 K48 linked polyubiquitination.
| 1 9

reach
More importantly, USP11 could promote cell growth and metastasis in colorectal cancer [XREF_BIBR, XREF_BIBR].

reach
For example, the aberrant expression of USP11 was found to interact with nuclear factor 90 and promote its deubiquitination, to promote the proliferation and metastasis of hepatocellular carcinoma.

reach
The E2F1 and USP11 positive feedback loop promotes hepatocellular carcinoma metastasis and inhibits autophagy by activating ERK and mTOR pathway.

eidos
Additionally , USP11 could promote cell proliferation and metastasis via regulating nuclear factor 90 ( NF90 ) in hepatocellular carcinoma [ 37 ] .

reach
USP11 promoted tumor growth and metastasis in CRC via the ERK and MAPK pathway by stabilizing PPP1CA, suggesting USP11 is a potential prognostic marker.

reach
Namely, USP11 has been shown to promote the proliferation and metastasis of hepatocellular carcinoma (HCC), but the underlying molecular basis is poorly understood.

reach
USP11 promotes growth and metastasis of colorectal cancer via PPP1CA mediated activation of ERK and MAPK signaling pathway.

reach
Overall, we suggest that USP11 promotes HCC cell metastasis, and we provide the first evidence of the prognostic significance of USP11 expression in HCC, which suggests that USP11 is a promising therapeutic target for the treatment of HCC.

reach
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.

reach
Additionally, USP11 could promote cell proliferation and metastasis via regulating nuclear factor 90 (NF90) in hepatocellular carcinoma [XREF_BIBR].
| 3 6
Mitoxantrone inhibits USP11.
| 3 5
| 3 5

reach
Moreover, inhibition of USP11 by Mitoxantrone (It was original developed as type II DNA topoisomerase inhibitor.

reach
Burkhart et al., using a fluorescent based high-throughput assay, screened more than 2000 FDA approved chemical entities and reported that mitoxantrone inhibits USP11 activity under in-vitro conditions.

sparser
Our observation that depletion of USP11 or inhibition of USP11 by a non-specific USP11 inhibitor Mitoxantrone significantly sensitized triple negative breast cancer cells to the chemo-drug cisplatin further supports USP11 as a potential target for anti-cancer treatment.

reach
We first determined whether mitoxantrone inhibits USP11 deubiquitinase activity.

reach
Mitoxantrone (MX), an anti-cancer drug, was reported to inhibit USP11.

reach
Mitoxantrone inhibits USP11 thus offering opportunities for targeting the BRCA1-MYCN interaction [148].
| PMC

sparser
Moreover, inhibition of USP11 by Mitoxantrone (It was original developed as type II DNA topoisomerase inhibitor.

sparser
Indeed, depletion of USP11 or inhibition of USP11 by a non-specific inhibitor Mitoxantrone led to significantly sensitization of triple negative breast cancer cells to the chemo-therapeutic agent cisplatin further confirming the therapeutic value of targeting USP11.
Mitoxantrone activates USP11.
| 1
| 1

reach
87,107,108 Mitoxantrone, a PARPi that targets the USP11 key enzyme that interacts with BRCA2, has been shown to be 40- to 20,000-fold more potent than the current gemcitabine first-line treatment in 2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP11 affects NFKBIA
| 1 2
USP11 inhibits NFKBIA.
| 1
USP11 inhibits NFKBIA. 1 / 7
| 1

eidos
For example , USP11 negatively regulates TNFalpha-induced NF-kappaB activation associated with IkappaBalpha and attenuates IkappaBalpha degradation [ 34 ] ; USP20 deubiquitinates TRAF6 and suppresses interleukin 1beta ( IL-1beta ) - and Tax-induced NF-kappaB activation [ 40 ] ; Katrin et al. showed that USP15 regulates IkappaBalpha / NF-kappaB by deubiquitinylation IkappaBalpha [ 44 ] ; and USP31 inhibits TNFalpha , CD40 , TRAF2 , TRAF6 and IKKbeta-mediated NF-kappaB activation [ 45 ] .
USP11 activates NFKBIA.
| 2
USP11 activates NFKBIA. 2 / 2
| 2

reach
Interestingly, knockdown of both USP15 and USP11 expression leads to an increased basal protein level of IkappaBalpha, suggesting that USP11 and USP15 cooperatively modulate IkappaBalpha turnover.

reach
USP11 is able to modulate TNF-alpha-induced NF-kappaB activation through regulation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) stability.
USP11 affects NONO
| 1 8
USP11 increases the amount of NONO.
| 6
USP11 increases the amount of NONO. 5 / 5
| 5

reach
Whereas, overexpression of USP11 increases NONO levels in a dose dependent manner.

reach
As a result, the knockdown of USP11 decreases NONO levels.

reach
As a result, exogenous USP11 increased NONO levels by preventing its ubiquitination.

reach
As a result, USP11 positively regulated NONO levels by protecting it from ubiquitin dependent degradation.

reach
By contrast, knockdown of USP11 decreased NONO levels, which was accompanied by increased ubiquitination.
Modified USP11 increases the amount of NONO. 1 / 1
| 1

reach
Whereas, overexpression of USP11 increases NONO levels in a dose dependent manner.
USP11 activates NONO.
| 1 2
USP11 activates NONO. 3 / 3
| 1 2

reach
Neither USP11 overexpression nor depletion in SK-Mel-28 and A375 cells had significant influence on NONO mRNA levels, indicating that USP11 positively regulates NONO at the protein levels, but not at the transcriptional levels.

reach
As anticipated, overexpression of USP11 could up-regulate NONO in the absence of MG132, whereas MG132 pretreatment effectively eliminated USP11 mediated change of NONO levels.

eidos
As a result , the knockdown of USP11 decreases NONO levels .
Notch affects USP11
| 6
Notch inhibits USP11.
| 2
Notch inhibits USP11. 2 / 4
| 2

reach
We further showed that USP11 is transcriptionally repressed by the Notch effector Hey1.

reach
In line with this notion, we showed that mouse Usp11 was repressed by the Notch and Hes1 axis, as overexpression of an active form of Notch (Notch intracellular domain, referred to as NIC) or Hes1 in a neuroblastoma cell line N2a diminished Usp11 expression and the promoter activity of Usp11 gene.
Notch decreases the amount of USP11.
| 4
Notch decreases the amount of USP11. 3 / 3
| 3

reach
However, it was recently demonstrated that Notch and Hey1 transcriptionally represses the expression of the PML deubiquitinase USP11, thereby down-regulating PML protein levels.

reach
Since our previous study found that human USP11 transcription is repressed by the Notch pathway, the up-regulation of Usp11 is likely a consequence of Notch inactivation upon the induction of neuronal differentiation.

reach
In line with this notion, we showed that mouse Usp11 was repressed by the Notch and Hes1 axis, as overexpression of an active form of Notch (Notch intracellular domain, referred to as NIC) or Hes1 in a neuroblastoma cell line N2a diminished Usp11 expression and the promoter activity of Usp11 gene.
Modified Notch decreases the amount of USP11. 1 / 1
| 1

reach
Accordingly, overexpression of constitutively active Notch (Notch intracellular domain, referred as NIC) in U87 and U251 cells downregulated USP11 and PML expression (XREF_FIG).
USP11 affects NFkappaB
| 5
USP11 inhibits NFkappaB.
| 2
| 1

reach
NF-kappaB signaling is negatively regulated by USP11 or USP15 mediated removal of K48 linked ubiquitin chains from IkappaBalpha [XREF_BIBR, XREF_BIBR].
Modified USP11 inhibits NFkappaB. 1 / 1
| 1

reach
Inhibition of USP11 expression reduces p53 levels and IKKalpha expression, as well as increasing the response of the NF-kappaB pathway to TNFalpha.
USP11 activates NFkappaB.
| 3
| 2

reach
USP11 is able to modulate TNF-alpha-induced NF-kappaB activation through regulation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) stability.

reach
However, down-regulation of USP11 dramatically enhances NF-kappaB activity in response to tumor necrosis factor-alpha, indicating that IKKalpha does not require activation of NF-kappaB.
USP11-C318A activates NFkappaB. 1 / 1
| 1

reach
However, we found that overexpression of USP11 C318A mutant only partially rescued the inhibitory effect of USP11-WT on TNFalpha induced IkappaBalpha ubiquitination (XREF_SUPPLEMENTARY) as well as TNFalpha- and IKKbeta induced NF-kappaB activation (XREF_SUPPLEMENTARY).
USP11 affects mgl-1
| 8
USP11 decreases the amount of mgl-1.
| 3
USP11 decreases the amount of mgl-1. 2 / 2
| 2

reach
Previously, we confirmed that depletion of USP11 decreases the expression level of Mgl-1 and increases the tumor cell growth.

reach
As expected, the depletion of USP11 decreased Mgl-1 expression and increased ubiquitination level of Mgl-1, but the mRNA level of Mgl-1 was decreased by the depletion of USP11.
USP11-C266S decreases the amount of mgl-1. 1 / 1
| 1

reach
In contrast, a catalytic mutant USP11 (C266S) and USP49 which were used as negative controls, failed to reduce the ubiquitination level of Mgl-1.
USP11 activates mgl-1.
| 2
USP11 activates mgl-1. 2 / 2
| 2

reach
Interestingly, RanBPM knockdown by RanBPM shRNA prevented USP11 induced Mgl-1 cell migration in the MDCK cells.

reach
Interestingly, the expression of USP11 increased the stability of Mgl-1 protein to some extent.
USP11 increases the amount of mgl-1.
| 2
Modified USP11 increases the amount of mgl-1. 1 / 1
| 1

reach
Endogenous Mgl-1 level was decreased by knockdown of RanBPM; however, overexpression of USP11 promotes the level of Mgl-1 as previously observed.
USP11 increases the amount of mgl-1. 1 / 1
| 1

reach
As expected, the depletion of USP11 decreased Mgl-1 expression and increased ubiquitination level of Mgl-1, but the mRNA level of Mgl-1 was decreased by the depletion of USP11.
USP11 inhibits mgl-1.
| 1
USP11 inhibits mgl-1. 1 / 1
| 1

reach
However, USP11 mediated Mgl-1 stabilization was inhibited in RanBPM-knockdown cells.
| 7

reach
Thus, we hypothesized that USP11 could promote resistance to 5-Fu in colorectal cancer by inducing autophagy.

reach
The results showed that USP11 overexpression significantly enhanced the resistance of HCT8 cells to 5-Fu compared with the control group, whereas the opposite effect was observed in USP11 knockdown HCT116 cells (P < 0.05, Student 's t test).

reach
In our study, the resistance to 5-Fu induced by USP11 can be weakened by VCP knockdown or autophagy inhibitors.

reach
The above experimental results have confirmed that USP11 could not only mediate the resistance to 5-Fu, but also induce autophagy in colorectal cancer cells.

reach
The experimental results showed that USP11 overexpression could enhance CRC cells resistance to 5-Fu, and knockdown of USP11 could result in CRC cells being more vulnerable to 5-Fu.

reach
USP11 promotes 5-Fu resistance through inducing autophagy dependent on VCP.

reach
Taken together these data, we hypothesized that USP11 might mediate resistance to 5-Fu by inducing autophagy in colorectal cancer cells and verified the hypothesis in follow-up experiments.
USP11 affects TP53
| 1 4
USP11 activates TP53.
| 1 2
USP11 activates TP53. 3 / 5
| 1 2

eidos
Inhibition of USP11 expression reduces p53 levels and IKKalpha expression , as well as increasing the response of the NF-kappaB pathway to TNFalpha ( 197 ) .

reach
A pro inflammatory mediator USP11 enhances the stability of p53 and inhibits KLF2 in intracerebral hemorrhage.

reach
Further, rescue experiments were conducted invivo to validate the function of the USP11/p53/KLF2/NF-kappaB axis in ICH induced inflammation, which confirmed that USP11 silencing blocked the release of pro inflammatory cytokines following ICH by downregulating p53, thus protecting against neurological impairment.
USP11 inhibits TP53.
| 1
USP11 inhibits TP53. 1 / 1
| 1

reach
Moreover, down-regulation of USP11 dramatically attenuated p53 induction in response to DNA damage stress.
USP11 increases the amount of TP53.
| 1
Modified USP11 increases the amount of TP53. 1 / 1
| 1

reach
Inhibition of USP11 expression reduces p53 levels and IKKalpha expression, as well as increasing the response of the NF-kappaB pathway to TNFalpha.
USP11 affects PML
| 7
USP11 activates PML.
| 3
USP11 activates PML. 3 / 3
| 3

reach
USP11 also increased PML half-life (XREF_FIG).

reach
Recent studies have demonstrated the pivotal roles of ubiquitination in PML stability mediated by an E3 ligase UHRF1 or deubiquitinase USP11 in cancers XREF_BIBR, XREF_BIBR.

reach
These data indicate that USP11 upregulates PML by preventing its proteasomal degradation.
USP11 inhibits PML.
| 2
USP11 inhibits PML. 2 / 2
| 2

reach
While USP40 shRNAs did not affect PML expression (XREF_SUPPLEMENTARY), knockdown of USP11 by three independent shRNAs induced downregulation of PML protein but not PML messenger RNA (XREF_FIG).

reach
USP11 mediated PML stabilization blocks GBM malignant traits.
USP11 increases the amount of PML.
| 1
Modified USP11 increases the amount of PML. 1 / 1
| 1

reach
This overexpression of USP11 increased PML levels (XREF_FIG) and decreased several GBM malignant traits, such as cell proliferation, migration and invasion (XREF_FIG).
USP11 decreases the amount of PML.
| 1
USP11 decreases the amount of PML. 1 / 1
| 1

reach
In the reciprocal experiment, USP11 depletion in a low-grade glioma cell line H4 not only reduced PML levels but also promoted cell proliferation, migration and invasion (XREF_FIG).
USP11 affects KLF4
| 2 1 3
USP11 inhibits KLF4.
| 2 2
USP11 inhibits KLF4. 4 / 4
| 2 2

reach
USP11 degrades KLF4 via its deubiquitinase activity in liver diseases.

reach
We also provide mechanistic insights into KLF4 degradation and show that USP11 depletion inhibits growth and chemoresistance of HCC cells by enhancing KLF4 stability.

eidos
USP11 degrades KLF4 via its deubiquitinase activity in liver diseases .

eidos
USP11 destabilizes KLF4 through the removal of K63-dependent polyubiquitination , thereby inhibiting KLF4 expression .
USP11 decreases the amount of KLF4.
| 1 1
USP11 decreases the amount of KLF4. 2 / 2
| 1 1

reach
USP11 inhibits KLF4 expression by cleaving K63-linked polyubiquitin chains in HepG2 hepatocarcinoma cells [34].
| PMC

trips
USP11 degrades KLF4 via its deubiquitinase activity in liver diseases.
USP11 affects USP11
| 4
USP11 decreases the amount of USP11.
| 2
USP11 decreases the amount of USP11. 2 / 4
| 2

reach
To investigate whether down-regulation of USP11 exhibits protective effects against LPS induced lung injury, USP11 levels in the mouse lungs were down-regulated by usp11 shRNA in a lentiviral vector delivery system (XREF_FIG d).

reach
To investigate whether USP11 modulates LPS induced signaling, USP11 expression was down-regulated by usp11 shRNA transfection.
USP11 inhibits USP11.
| 1
USP11 inhibits USP11. 1 / 1
| 1

reach
Furthermore, there is a rapid loss of USP11 upon DNA damage induction, specifically in G1 phase (XREF_FIG and XREF_FIG).
USP11 increases the amount of USP11.
| 1
Modified USP11 increases the amount of mutated USP11. 1 / 1
| 1

reach
As shown in XREF_FIG B & C, while elevated expression of wild-type USP11 led to transformation of MCF10A and increased acini overgrowth, the expression of mutant USP11 without catalytic activity (Cys318 is replaced by Ala) failed to promote colony formation as well as acini overgrowth.
| 6
5-formyluracil inhibits USP11.
| 3

reach
The results showed that overexpression of VCP inhibited reduced cell viability caused by USP11 knockdown when treated with 5-Fu.

reach
To investigate whether USP11 is related to autophagy, rapamycin and 5-Fu were used to stimulate USP11 knockdown and overexpressing cells.

reach
In this study, we found that the autophagy of colorectal cancer cells with overexpression of USP11 was significantly enhanced after treated with 5-Fu, while the autophagy of colorectal cancer cells with knockdown of USP11 was significantly weakened after treated with 5-Fu.
5-formyluracil increases the amount of USP11.
| 2
5-formyluracil increases the amount of USP11. 2 / 2
| 2

reach
After 48 hours of treatment with different concentrations of 5-Fu, we found that 5-Fu dramatically upregulated USP11 expression in a dose dependent manner in HCT8 cells.

reach
What 's more, 5-Fu treatment could increase the expression level of USP11 but had no effect on VCP.
5-formyluracil activates USP11.
| 1

reach
In this study, we found that the autophagy of colorectal cancer cells with overexpression of USP11 was significantly enhanced after treated with 5-Fu, while the autophagy of colorectal cancer cells with knockdown of USP11 was significantly weakened after treated with 5-Fu.
USP11 affects translation
| 5
| 5

reach
Overexpression of either eIF4B or USP11 significantly enhanced both cap dependent as well as IRES mediated translation in a dose dependent manner.

reach
USP11 stimulates translation.

reach
Ectopic expression of USP11 (W) or USP11 S453D, but not USP11 S453A, enhanced the overall mRNA translation in DLBCLs.

reach
We further demonstrated that USP11 activity stabilizes eIF4B protein levels and stimulates oncogenic translation.

reach
Indeed, USP11 was noted to be phosphorylated by S6Kinase that increases its interaction with eIF4B and subsequently enhanced cancer promoting gene translation.
| 5

reach
USP11 inhibits viral RNA replication through deubiquitinating on K184 of NP.

reach
When cellular USP11 was knocked down, the amounts of vRNA and cRNA of the wild-type virus increased by about 2.5-fold ( Figure 7A, lane 1 versus lanes 2 and 3) , indicating that USP11 inhibits viral RNA replication as previously mentioned; with the mutant virus defective in NP ubiquitination (K184R), however, there was no significant difference in viral RNA synthesis between USP11 knockdown and control cells ( Figure 7A, lanes 4-6) .

reach
Conversely, overexpression of USP11 specifically inhibited viral genomic RNA replication, and this inhibition required the deubiquitinase activity.

reach
Significantly, USP11 can cleave single ubiquitin from NP, and thereby inhibit the RNA replication efficiency ( Figure 8B ).

reach
This result further supports the conclusion that USP11 inhibits viral RNA replication through deubiquitinating NP.Ubiquitination is a posttranslational modification, in which ubiquitin chains or single ubiquitin molecules are linked to target proteins, giving rise to poly-or monoubiquitination (Weissman, 2001) .
HDAC2 affects USP11
| 5
HDAC2 inhibits USP11. 5 / 5
| 5

reach
The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells (Fig. 5f, i).

reach
In our study, the concurrent inhibition of HDAC1 and HDAC2 upregulated USP11 and induced G1/S transition arrest in GBM cells in vitro and in vivo.

reach
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells performed and showed that USP11 expression was downregulated at the mRNA and protein levels in U87, U251 and N9 cells upon the activation of EGFR-vIII (Fig. 5c, d) .

reach
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cellsFig.

reach
The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells.
HDAC1 affects USP11
| 5
HDAC1 inhibits USP11. 5 / 5
| 5

reach
The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells.

reach
In our study, the concurrent inhibition of HDAC1 and HDAC2 upregulated USP11 and induced G1/S transition arrest in GBM cells in vitro and in vivo.

reach
The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells (Fig. 5f, i).

reach
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cellsFig.

reach
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells performed and showed that USP11 expression was downregulated at the mRNA and protein levels in U87, U251 and N9 cells upon the activation of EGFR-vIII (Fig. 5c, d) .
PI3K affects USP11
| 5
PI3K decreases the amount of USP11.
| 3
PI3K decreases the amount of USP11. 3 / 3
| 3

reach
Emerging evidence has shown that the PI3K and AKT pathway can inhibit USP11 transcription and translation.

reach
Emerging evidence has shown that the PI3K/AKT pathway can inhibit USP11 transcription and translation.

reach
e, h PI3K/AKT pathway inhibition upregulated the transcription and translation of USP11 in U87-vIII, U251-vIII and N9-vIII cells.
PI3K activates USP11.
| 2
PI3K activates USP11. 2 / 2
| 2

reach
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K and AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11.

reach
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K/AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11 (Fig. 5e, h).
AKT affects USP11
| 5
AKT decreases the amount of USP11.
| 3
AKT decreases the amount of USP11. 3 / 3
| 3

reach
Emerging evidence has shown that the PI3K and AKT pathway can inhibit USP11 transcription and translation.

reach
e, h PI3K/AKT pathway inhibition upregulated the transcription and translation of USP11 in U87-vIII, U251-vIII and N9-vIII cells.

reach
Emerging evidence has shown that the PI3K/AKT pathway can inhibit USP11 transcription and translation.
AKT inhibits USP11.
| 2
AKT inhibits USP11. 2 / 2
| 2

reach
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K and AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11.

reach
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K/AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11 (Fig. 5e, h).
4 |
Valproic acid decreases the amount of USP11. 4 / 4
4 |

ctd
No evidence text available

ctd
No evidence text available

ctd
No evidence text available

ctd
No evidence text available
USP11 affects ferroptosis
| 1 3
| 1 3

reach
Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis.

reach
Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11 -/Y ) significantly decreased neuronal cell ferroptosis.

eidos
Interestingly , upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux , a potential mechanism through which USP11 may enhance ferroptosis .

reach
The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11.
USP11 affects cell cycle
| 4
USP11 inhibits cell cycle.
| 2
| 2

reach
Deng and his colleagues found that the deubiquitinase USP11 could inhibit cell cycle progression from G1 to S phase though stabilizing P21 [XREF_BIBR].

reach
Deng and his colleagues found that the deubiquitinase USP11 could inhibit cell cycle progression from G1 to S phase though stabilizing P21 [25].
USP11 activates cell cycle.
| 2
| 2

reach
Our data indicated that the Usp11 deficiency increased cell cycle length of NPCs at E12.5 (XREF_FIG).

reach
The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines.
USP11 affects PCGF2
1 | 3
USP11 activates PCGF2.
| 3
USP11 activates PCGF2. 3 / 3
| 3

reach
Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins.

reach
Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins [XREF_BIBR].

reach
Importantly, knockdown of either USP7 or USP11 reduces the total and chromatin bound pool of BMI1 and MEL18, and the effects can be mitigated by inhibiting proteasome function.
USP11 increases the amount of PCGF2.
1 |
Catalytically active USP11 increases the amount of PCGF2. 1 / 1
1 |

bel
Regulation of the stability of the PRC1 complex also appears to be another facet, as the de-ubiquitination of the PRC1 components BMI1 and MEL18 by the ubiquitin-specific proteases 7 and 11 has been shown to increase their abundance (Maertens et al., 2010), whereas the loss of these ubiquitin-specific proteases promotes INK4A transcriptional activation.
USP11 affects BMI1
1