OTUD6B Data Analysis

HGNC Gene Name
OTU deubiquitinase 6B
HGNC Gene Symbol
OTUD6B
Identifiers
hgnc:24281 NCBIGene:51633 uniprot:Q8N6M0
Orthologs
mgi:1919451 rgd:1310024
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for OTUD6B
Number of Papers
36 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
CNGB3 cyclic nucleotide gated channel subunit beta 3 0.211
SLC26A7 solute carrier family 26 member 7 0.21
AUNIP aurora kinase A and ninein interacting protein 0.198
IKBKG inhibitor of nuclear factor kappa B kinase regulatory subunit gamma -0.191 0.64 3.42 2.78e-40
KIF24 kinesin family member 24 0.189
TRHR thyrotropin releasing hormone receptor 0.185
GUCA1C guanylate cyclase activator 1C 0.183

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with OTUD6Busing 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

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out OTUD6B using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
CAV1 caveolin 1 5.69e-01 1.89e-09 7.73e-06
RPS21 ribosomal protein S21 8.25e-01 1.09e-08 2.23e-05
RPL22 ribosomal protein L22 6.41e-01 6.81e-07 9.31e-04
NUDT4 nudix hydrolase 4 -4.67e-01 1.22e-06 1.25e-03
EIF5A eukaryotic translation initiation factor 5A -6.00e-01 7.93e-06 6.50e-03
COPS4 COP9 signalosome subunit 4 5.44e-01 2.72e-05 1.86e-02
HNRNPH1 heterogeneous nuclear ribonucleoprotein H1 -4.14e-01 4.41e-05 2.48e-02
UBE2N ubiquitin conjugating enzyme E2 N -3.18e-01 4.84e-05 2.48e-02
MYL12A myosin light chain 12A 2.43e-01 1.02e-04 4.67e-02

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to OTUD6B 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
OTUD6B leads to the deubiquitination of VHL. 1 / 1
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Surprisingly, OTUD6B limits the ubiquitylation of pVHL independent of its deubiquitylase activity.

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
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In the hormone receptor positive cell line HCC1500 (ER positive) silencing STK39 decreased survival (p = 0.03) and silencing OTUD6B increased apoptosis (p = 0.02) (XREF_FIG and XREF_FIG).

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Overexpressing Otud-6B in Ba/F3 cells resulted in downregulation of proliferation and increased the frequency of apoptosis [96].

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Overexpressing Otud-6B in Ba/F3 cells resulted in downregulation of proliferation and increased the frequency of apoptosis [XREF_BIBR].

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In the HER2 positive cell line SKBR3, silencing all three early stage antigens decreased survival (PDHX and STK39 p < 0.0001 and OTUD6B p = 0.05) and both STK39 and OTUD6B increased apoptosis (STK39 p = 0.0002 and OTUD6B p < 0.0001).
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In the HER2 positive cell line SKBR3 , silencing all three early stage antigens decreased survival ( PDHX and STK39 p < 0.0001 and OTUD6B p =0 .05 ) and both STK39 and OTUD6B increased apoptosis ( STK39 p =0 .0002 and OTUD6B p < 0.0001 ) .
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Valproic acid increases the amount of OTUD6B. 2 / 2
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Bisphenol A decreases the amount of OTUD6B. 2 / 2
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Further, lncRNA OTUD6B can inhibit ccRCC cell proliferation by suppressing the Wnt and beta-catenin pathway and the expressions of epithelial-to-mesenchymal transition related proteins.

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In normal and transformed cells, the expression of the OTUD6B isoform that represses protein synthesis and proliferation is quantitatively higher.

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Additionally, OTUD6B depletion increased AHA incorporation in H1734 and H1437 cells, and in transformed or primary cells other than NSCLC, specifically the mesothelioma cell line ME16, HaCaT immortalized human keratinocytes, and primary lung fibroblasts WI38 (XREF_FIG).

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Furthermore, NSCLC exposure to Torin-1 (an mTOR inhibitor, which target the mTOR catalytic site) abolished OTUD6B depletion enhanced AHA incorporation in these cells (XREF_FIG).
Urethane affects OTUD6B
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Urethane decreases the amount of OTUD6B. 1 / 1
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Trimellitic anhydride increases the amount of OTUD6B. 1 / 1
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Titanium dioxide decreases the amount of OTUD6B. 1 / 1
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Thioacetamide increases the amount of OTUD6B. 1 / 1
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Thimerosal affects OTUD6B
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Thimerosal increases the amount of OTUD6B. 1 / 1
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Tetrachloromethane increases the amount of OTUD6B. 1 / 1
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Schizandrin B increases the amount of OTUD6B. 1 / 1
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Quercetin affects OTUD6B
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Quercetin decreases the amount of OTUD6B. 1 / 1
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Pirinixic acid increases the amount of OTUD6B. 1 / 1
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siRNAs to OTUD6B were unable to modify AHA incorporation when cells were treated with cycloheximide or homoharringtonine (XREF_FIG, left).
Ionomycin affects OTUD6B
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Ionomycin increases the amount of OTUD6B. 1 / 1
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Dicrotophos decreases the amount of OTUD6B. 1 / 1
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Cyclosporin A increases the amount of OTUD6B. 1 / 1
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Clothianidin increases the amount of OTUD6B. 1 / 1
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Carbon nanotube increases the amount of OTUD6B. 1 / 1
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Benzo[a]pyrene increases the amount of OTUD6B. 1 / 1
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Aflatoxin B1 increases the amount of OTUD6B. 1 / 1
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TNFSF13B affects OTUD6B
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TNFSF13B increases the amount of OTUD6B. 1 / 1
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BAFF, a B cell activating factor of the TNF family, could also induce Otud-6b expression on mouse B cells after 4 hours stimulation XREF_BIBR.
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OTUD6B depletion caused an increased rate of cap dependent translation.
OTUD6B affects cell cycle
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However, the rapid down-regulation of Otud-6b is probably required to maintain a normal cell cycle as enforced Otud-6b expression can cause cell cycle arrest in Ba/F3 cells.
OTUD6B affects Wnt
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OTUD6B activates Wnt. 1 / 1
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Further, lncRNA OTUD6B can inhibit ccRCC cell proliferation by suppressing the Wnt and beta-catenin pathway and the expressions of epithelial-to-mesenchymal transition related proteins.
OTUD6B affects TRAF6
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OTUD6B bound to IRF3 inhibits TRAF6. 1 / 1
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Further assays indicate that otud6b interacts with irf3 and irf7 and diminishes traf6 mediated K63 linked polyubiquitination of irf3 and irf7.
OTUD6B affects TBK1
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OTUD6B inhibits TBK1. 1 / 1
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Moreover, otud6b also attenuates tbk1 to bind to irf3 and irf7, resulting in the impairment of irf3 and irf7 phosphorylation.
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Disruption of otud6b in zebrafish increases the survival rate upon spring viremia of carp virus and grass carp reovirus exposure .

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More interestingly, another major finding was that the molecular mechanism involved lncRNA OTUD6B-AS1 inhibition of IDH2 expression through stabilization of miR-6734-5p ( xref ).

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Deubiquitylase OTUD6B Governs pVHL Stability in an Enzyme Independent Manner and Suppresses Hepatocellular Carcinoma Metastasis.
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In 2017, Autosomal recessive mutations of OTUD6B were first described to cause intellectual disability associated with seizure, dysmorphic features, and congenital malformations, including distal limb abnormalities.
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OTUD6B affects HIF1A
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OTUD6B bound to VHL activates HIF1A. 1 / 1
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OTUD6B directly interacts with pVHL, decreases its ubiquitylation and proteasomal degradation to reduce HIF-1alpha accumulation in HCC cells under hypoxia.
OTUD6B affects Cyclin
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OTUD6B activates Cyclin. 1 / 1
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Nevertheless, OTUD-6B probably could directly affect either the synthesis or the degradation process of cyclin D2 as overexpressing OTUD-6B in Hela cells could also cause cyclin D2 expression level down-regulation even without affecting cell cycle (XREF_SUPPLEMENTARY).
OTUD6B affects CTNNB1
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OTUD6B activates CTNNB1. 1 / 1
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Further, lncRNA OTUD6B can inhibit ccRCC cell proliferation by suppressing the Wnt and beta-catenin pathway and the expressions of epithelial-to-mesenchymal transition related proteins.
OTUD6B affects CD3
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OTUD6B inhibits CD3. 1 / 1
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For mice vaccinated with Pdhx, Stk39, and Otud6B depletion of CD3 + T cells increased tumor growth (p < 0.0001 compared to empty vector control for all targets).
NRF1 affects OTUD6B
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NRF1 decreases the amount of OTUD6B. 1 / 1
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MT19c compound increases the amount of OTUD6B. 1 / 1
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IL4 affects OTUD6B
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IL4 activates OTUD6B. 1 / 1
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Here we report that Otud-6b, a functional DUB of the OTU family, can be induced by IL-3, IL-4, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulation in B lymphocytes.
IL3 affects OTUD6B
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IL3 activates OTUD6B. 1 / 1
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Here we report that Otud-6b, a functional DUB of the OTU family, can be induced by IL-3, IL-4, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulation in B lymphocytes.
IL2 affects OTUD6B
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IL2 increases the amount of OTUD6B. 1 / 1
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On the other hand, IL-2 could not induce Otud-6b expression in Ba/F3 cells (XREF_SUPPLEMENTARY).
IL13 affects OTUD6B
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IL13 activates OTUD6B. 1 / 1
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Here we report that Otud-6b, a functional DUB of the OTU family, can be induced by IL-3, IL-4, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulation in B lymphocytes.
CSF3 affects OTUD6B
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CSF3 decreases the amount of OTUD6B. 1 / 1
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However, granulocyte colony stimulating factor (G-CSF) could effectively down-regulate OTUD-6B expression when human leukocytes were stimulated for 16 hours XREF_BIBR.
CSF2 affects OTUD6B
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CSF2 activates OTUD6B. 1 / 1
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Here we report that Otud-6b, a functional DUB of the OTU family, can be induced by IL-3, IL-4, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulation in B lymphocytes.
17alpha-ethynylestradiol increases the amount of OTUD6B. 1 / 1
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