OTULIN Data Analysis

HGNC Gene Name
OTU deubiquitinase with linear linkage specificity
HGNC Gene Symbol
OTULIN
Identifiers
hgnc:25118 NCBIGene:90268 uniprot:Q96BN8
Orthologs
mgi:3577015 rgd:2324500
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for OTULIN
Number of Papers
89 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
DNAH5 dynein axonemal heavy chain 5 0.289 -0.16 -0.94 1.12e-02
TRIO trio Rho guanine nucleotide exchange factor 0.285 Reactome (2) 0.24 1.21 2.62e-05
OTULINL OTU deubiquitinase with linear linkage specificity like 0.269 INDRA (1)
FBXL7 F-box and leucine rich repeat protein 7 0.238 Reactome (2)
BBS9 Bardet-Biedl syndrome 9 0.232 0.39 2.06 2.63e-06
KRTAP12-1 keratin associated protein 12-1 0.223
C19orf33 chromosome 19 open reading frame 33 -0.22

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with OTULINusing 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 OTULIN 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
Modified OTULIN-C129A leads to the deubiquitination of RNF31 on M1. 1 / 1
| 1

reach
We have previously shown that knockdown of OTULIN or overexpression of a catalytically inactive OTULIN C129A mutant (CA) lead to the autoubiquitination of HOIP with Met1 linked polyUb chains (XREF_FIG A, compare lanes 1 and 4; XREF_FIG B, compare lanes 1 and 2).
OTULIN leads to the deubiquitination of RNF31. 1 / 1
| 1

reach
This observation suggests that, under basal conditions, the binding of OTULIN prevents HOIP autoubiquitination.
OTULIN leads to the deubiquitination of RIPK1. 1 / 1
| 1

reach
OTULIN reduced ubiquitination of both, caspase-8 and RIPK1, identifying RIPK1 and caspase-8 as linearly ubiquitinated proteins (Fig XREF_FIG A).
OTULIN deubiquitinates Proteasome. 1 / 1
| 1

reach
Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production.
OTULIN deubiquitinates IKBKG. 1 / 1
|

ubibrowser
Deubiquitination effects of swine OTULIN were identified. The interaction between porcine OTULIN and PRRSV Nsp11 is dependent on the OTU domain. PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to promote removal of linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I IFNs.
OTULIN leads to the deubiquitination of CASP8. 1 / 1
| 1

reach
OTULIN reduced ubiquitination of both, caspase-8 and RIPK1, identifying RIPK1 and caspase-8 as linearly ubiquitinated proteins (Fig XREF_FIG A).
OTULIN deubiquitinates IRF3. 1 / 1
| 1

reach
The antiviral action of the RIG-I induced pathway of apoptosis (RIPA) is enhanced by its ability to degrade Otulin, which deubiquitinates IRF3.
OTULIN deubiquitinates ACVRL1. 1 / 1
| 1

reach
Conversely, OTULIN deubiquitinates ALK1 to promote Smad1/5 activation.
OTULIN deubiquitinates NLRP6. 1 / 1
| 1

reach
Cyld cleaved Ub chains from NLRP6 (XREF_FIG, top blot, lane 2) and released Ub (XREF_FIG, bottom blot, lane 2), whereas otulin failed to deubiquitinate NLRP6 (XREF_FIG, top blot, lane 3).
OTULIN deubiquitinates OTULINL. 1 / 1
| 1

reach
Intriguingly, the OTULIN pseudo deubiquitinating enzyme FAM105A (OTULINL) shares ~ 33% amino acid sequence identity with OTULIN, but lacks Met1 Ub catalytic activity or the ability to interact with Ub or LUBAC [XREF_BIBR, XREF_BIBR].

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
OTULIN affects NFkappaB
| 3 1 24
OTULIN inhibits NFkappaB.
| 2 1 16
| 2 1 14

reach
Nevertheless, the DUB OTULIN is identified to restrain the formation of M1 linked Ub chains on the bacterial coat, then sequester the recruitment of NEMO and ultimately inhibit NF-kappaB pathway.

eidos
OTULIN is upregulated in a PRRSV infection model and interacts with the PRRSV non-structural protein 11 ( Nsp11 ) to decrease Ub levels on NEMO and to block NF-kappaB activation and IFN-regulatory transcription factor 3 ( IRF3 ) - mediated type-I IFN production [ 22 ] .

reach
Overexpression of OTULIN inhibits TNF-alpha-induced NF-kappaB signaling by preventing the association of NEMO with polyubiquitinated RIP1 (Fiil et al., 2013; Keusekotten et al., 2013).

reach
It appears that OTULIN overexpression antagonizes NF-kappaB activation by removing Met1-polyUb, whereas OTULIN C129A acts as a high-affinity UBD that competes with other Met1 specific UBDs required for NF-kappaB signaling in a similar manner to the one recently reported for the overexpression of the NEMO UBAN domain.

reach
Loss of OTULIN expression in mouse hepatocytes increases cellular Met1 Ub levels, decreases LUBAC levels and does not induce NF-kappaB hyper-signaling, but sensitizes to apoptosis [XREF_BIBR, XREF_BIBR], in line with previous reports [XREF_BIBR, XREF_BIBR].

reach
As both CYLD and OTULIN negatively regulate the NF-kappaB signalling cascade, the impact of these deubiquitinases in different LUBAC dependent signalling cascades may be context dependent.

reach
For example, the deubiquitinases Gumby (OTULIN), OTUD7b, and TNFAIP3 (A20) in the OUT family were shown to negatively regulate NFkappaB activation through different mechanisms in different biological contexts [XREF_BIBR - XREF_BIBR].

reach
Moreover, OTULIN overexpression significantly attenuated NF-kappaB activity in the ischemic cortex, as determined by the inhibition of IkappaBalpha degradation and phosphorylation along with reduced nuclear translocation of p65, which manifested as less p65 in the nucleus and more p65 in the cytoplasm.

reach
To directly address if OTULIN antagonizes NF-kappaB activation by disassembling Met1-Ub, we devised a system whereby a noncleavable (Gly76 --> Ser76; GS) Met1-Ub was docked to XIAP via an IAP binding [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
Ectopic expression of OTULIN in HEK293 and HeLa cells inhibits LUBAC dependent NF-kappaB signaling, suggesting that OTULIN is a negative regulator of this signaling pathway 18, 20.
OTULIN bound to Nsp11 inhibits NFkappaB. 1 / 1
| 1

reach
OTULIN is upregulated in a PRRSV infection model and interacts with the PRRSV non structural protein 11 (Nsp11) to decrease Ub levels on NEMO and to block NF-kappaB activation and IFN-regulatory transcription factor 3 (IRF3)-mediated type-I IFN production [XREF_BIBR].
OTULIN-C129A inhibits NFkappaB. 1 / 1
| 1

reach
Interestingly, overexpression of catalytically inactive OTULIN C129A also suppressed NF-kappaB signaling, in contrast to the Ub binding mutant OTULIN W96A, likely due to the ability of OTULIN C129A to compete with endogenous UBDs involved in NF-kappaB signaling, as it is the case for Ub binding domain in ABIN proteins and NEMO (UBAN)-based Met1 Ub sensors as well [XREF_BIBR, XREF_BIBR].
OTULIN activates NFkappaB.
| 1 7
| 1 7

reach
Immune cell specific depletion of OTULIN leads to cell-type specific effects : constitutive active NF-kappaB signalling and overproduction of cytokines in myeloid cells, and down-regulation of linear ubiquitination signal in the B and T cells based on LUBAC degradation [XREF_BIBR].

reach
Mutation of Tyr56 in the OTULIN PIM domain abrogates HOIP binding, resulting in reduced ability of OTULIN to inhibit NF-kappaB activity and reduced cell death signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

reach
Small interfering RNA (siRNA) against OTULIN resulted in anincrease in LUBAC induced NF-kappaB activation in HEK 293ET and U2OS cells and also in T-REx 293 cells stably expressing a doxycycline inducible OTULIN targeting microRNA (miRNA) (XREF_FIG A and XREF_FIG A-S6C).

reach
The recently identified linear-chain-specific DUB OTULIN has been implicated in the regulation of TNF induced NF-kappaB activation and cell death XREF_BIBR.

reach
In contrast, depletion of OTULIN enhanced the activation of NF-kappaB in response to NOD2 stimulation 64.

reach
In contrast, OTULIN deficient myeloid cells are hyper-inflammatory and spontaneously activate NF-kappaB and secrete TNF.

reach
Primary fibroblast cultures from this patient reveal a surprising phenotype of deregulated M1 linked Ub signalling, whereby OTULIN loss coincides with LUBAC downregulation to prevent intrinsic NF-kappaB activation.

eidos
OTULIN targets Met1-linked Ub and counteracts LUBAC auto-ubiquitination , thereby promoting NF-kappaB activation and MAPK signaling .
OTULIN decreases the amount of NFkappaB.
| 1
Modified OTULIN decreases the amount of NFkappaB. 1 / 1
| 1

reach
Overexpression of OTULIN, and hence removal of all Met1 linkages from cells, blocks NF-kappaB translocation to the nucleus upon TNF stimulation and reduces NF-kappaB target gene expression.

reach
Interestingly, conditional deletion of otulin in myeloid cells, but not T or B cells, causes systemic inflammation, neutrophil infiltration, and multi-organ inflammation in mouse models.

reach
OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase Mediated Hepatocyte Apoptosis.

reach
Finally, the numerous other upregulated cytokines in LysMCre-OtulinLacZ and flox mice, which includes anti-inflammatory IL-10, will generate a delicate balance of responses, enabling these mice to deal with inflammation induced by loss of OTULIN.

reach
Deletion of Otulin in Mouse Immune Cells Drives Acute Systemic Inflammation.

reach
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice.

reach
In an acute model, induced loss of OTULIN in immune cells leads to multi-organ inflammation and deterioration of animals within a few days; this can be ameliorated by anti-TNF, but not by neutralization of other upregulated cytokines.

reach
OTULIN overexpression attenuated microglia activation in LPS induced brain inflammation.

reach
While loss of OTULIN leads to excessive inflammation through accumulation of linear-Ub, germline deficiencies of LUBAC also result in autoinflammation.

reach
OTULIN limits cell death and inflammation by deubiquitinating LUBAC.
| 5

reach
These cellular and molecular mediators are indicative of an inappropriate and damaging inflammatory response mediated by OTULIN deficient myeloid cells.

reach
Inactivation of OTULIN by expression of OTULIN C129A in adult mice has recently been reported to cause systemic inflammation, which can be prevented by combined ablation of cell death pathways by deletion of caspase-8, RIPK3 and RIPK1 (Heger etal, 2018).

reach
To exclude the possibility that the effect of OTULIN on reducing microglia activation is an indirect outcome of its neuroprotective role [XREF_BIBR], a commonly used LPS induced pure brain inflammation model without brain cell death served as a positive control.

reach
OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver.

reach
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice.
OTULIN affects cell death
| 1 10
OTULIN activates cell death.
| 6
| 6

reach
OTULIN deficiency sensitises fibroblasts and monocytes to TNF induced cell death.

reach
OTULIN overexpression or knockdown affects NF-kappaB responses to LUBAC, TNFalpha, and poly (I : C) and sensitizes cells to TNFalpha induced cell death.

reach
The recently identified linear-chain-specific DUB OTULIN has been implicated in the regulation of TNF induced NF-kappaB activation and cell death XREF_BIBR.

reach
During necroptosis, OTULIN is hyper-phosphorylated at Tyr 56, which modulates RIPK1 ubiquitin dynamics and promotes cell death.

reach
Surprisingly, overexpression of wild-type OTULIN abrogates the RIPK1-NEMO interaction and sensitizes to TNFalpha induced cell death, as well [XREF_BIBR].

reach
Moreover, stable overexpression of OTULIN sensitized cells to TNFalpha induced cell death (XREF_FIG D and 6E), consistent with observations in cpdm mice that lack Sharpin or in humans with mutations in HOIL1.
OTULIN inhibits cell death.
| 1 4
| 1 4

reach
This suggests that loss of OTULIN does not cause aberrant cell death in immune cells (XREF_FIG E) and that the high levels of cytokines and chemokines present activate the entire immune cell population.

reach
Mutation of Tyr56 in the OTULIN PIM domain abrogates HOIP binding, resulting in reduced ability of OTULIN to inhibit NF-kappaB activity and reduced cell death signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

eidos
Furthermore , Otulin inactivation reduces TNFR1 complex formation and increases cell death [ 83 ] .

reach
However, both overexpression and knockdown of OTULIN sensitized cells to TNFalpha induced cell death, suggesting more complex roles for Met1 linkages in balancing signaling pathways downstream of the TNFalpha receptor.

reach
OTULIN limits cell death and inflammation by deubiquitinating LUBAC.
OTULIN affects GZMM
| 10
OTULIN inhibits GZMM.
| 4
OTULIN inhibits GZMM. 4 / 4
| 4

reach
Contrary to this, OTULIN functions to restrict the accumulation of Met1-Ub at basal conditions and early during signaling, and OTULIN expression is not induced by stimulation of NF-kappaB activity.

reach
Conversely, OTULIN overexpression suppressed Met1-Ub of RIPK2 in a manner dependent on its catalytic activity.

reach
To directly address if OTULIN antagonizes NF-kappaB activation by disassembling Met1-Ub, we devised a system whereby a noncleavable (Gly76 --> Ser76; GS) Met1-Ub was docked to XIAP via an IAP binding [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
In contrast, our data suggest that OTULIN functions to restrict Met1-Ub accumulation and regulate early signaling processes.
OTULIN activates GZMM.
| 4
OTULIN activates GZMM. 3 / 3
| 3

reach
Accordingly, Met1-Ub on RIPK2 was largely inhibited by overexpressing OTULIN and was increased by OTULIN depletion.

reach
Nonetheless, OTULIN overexpression strongly impairs coprecipitation of ubiquitinated RIPK1 with NEMO in TNF treated cells, whereas small interfering RNA mediated depletion of OTULIN increases the early accumulation of Met1-Ub on RIPK1 XREF_BIBR.

reach
Activation of the MAP kinases p38 and JNK1/2 was only slightly increased by OTULIN depletion, consistent with the notion that OTULIN disassembles Met1-Ub primarily involved in IKK activation.
OTULIN-C129A activates GZMM. 1 / 1
| 1

reach
Accordingly, ectopic expression of inactive OTULIN (C129A), but not inactive CYLD (C601A), caused extensive accumulation of Met1-Ub on HOIP (XREF_FIG H and XREF_SUPPLEMENTARY F).
OTULIN decreases the amount of GZMM.
| 2
Modified OTULIN decreases the amount of GZMM. 2 / 2
| 2

reach
Accordingly, the amount of Met1-Ub on RIPK2 was decreased by overexpression of OTULIN and strongly enhanced in OTULIN depleted cells.

reach
Conversely, overexpression of OTULIN decreased the level of Met1-Ub in the TNF-RSC and reduced the apparent molecular weight of ubiquitinated TNFR1.
TNF affects OTULIN
| 8
TNF activates OTULIN.
| 6
TNF activates OTULIN. 6 / 6
| 6

reach
However, although A20 and CYLD are induced by TNFalpha for the establishment of a negative feedback loop, neither OTULIN (XREF_FIG F) nor LUBAC are induced by TNFalpha, again suggesting that they function as a differentially regulated signaling module.

reach
Importantly, similar effects were obtained when the OTULIN deficient patients were treated with the TNF antagonist infliximab.

reach
XREF_FIG E, cholera toxin strongly inhibited SNX27 mediated TNFalpha stimulation mediated OTULIN membrane localization.
| PMC

reach
Significantly, the fact that the here described OTULIN related autoinflammatory syndrome and ORAS can be treated with TNF neutralizing antibodies suggests a potential therapeutic strategy to treat conditions caused by excessive M1 linked polyUb signaling.

reach
XREF_FIG A, the interaction between endogenous SNX27 and OTULIN was upregulated when cells were treated with TNFalpha for 5min.
| PMC

reach
The deubiquitinase OTULIN removes methionine 1 (M1)-linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF driven inflammation in OTULIN related autoinflammatory syndrome (ORAS).
TNF inhibits OTULIN.
| 2
TNF inhibits OTULIN. 2 / 2
| 2

reach
XREF_FIG E, cholera toxin strongly inhibited SNX27 mediated TNFalpha stimulation mediated OTULIN membrane localization.
| PMC

reach
Similarly, overexpression of OTULIN reduces the clonogenic survival of cells treated with TNF XREF_BIBR.
OTULIN affects RIPK1
| 5
OTULIN inhibits RIPK1.
| 4
OTULIN inhibits RIPK1. 2 / 4
| 2

reach
Formation of the secondary, receptor-free cytoplasmic complex II is largely dependent on the activity of DUBs, specifically cylindromatosis (CYLD), A20 (also known as TNFAIP3) and ubiquitin thioesterase OTULIN, which destabilize complex I, abrogate NF-kappaB activation and release RIPK1 from complex I, which then forms the cytosolic complex II XREF_BIBR, XREF_BIBR.

reach
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice.
Mutated OTULIN inhibits RIPK1. 1 / 1
| 1

reach
Mutant OTULIN proteins can not restrict the accumulation of Met1 Ub chains on target substrates IKK and NEMO, RIPK1, and ASC.
OTULIN inhibits ubiquitinated RIPK1. 1 / 1
| 1

reach
Nonetheless, OTULIN overexpression strongly impairs coprecipitation of ubiquitinated RIPK1 with NEMO in TNF treated cells, whereas small interfering RNA mediated depletion of OTULIN increases the early accumulation of Met1-Ub on RIPK1 XREF_BIBR.
OTULIN activates RIPK1.
| 1
OTULIN activates RIPK1. 1 / 1
| 1

reach
OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase Mediated Hepatocyte Apoptosis.
OTULIN affects Ubiquitin
| 7
OTULIN inhibits Ubiquitin.
| 4
| 3

reach
OTULIN prevents such promiscuity by requiring a properly positioned Ub residue, Glu16, for catalytic efficiency.

reach
As expected, OTULIN treatment abolished the detection of ubiquitin chains (Fig XREF_FIG A, top panel), confirming that linear ubiquitination occurs in adult flies.

reach
In this study, the ‘deubiquitinase’ OTULIN was shown to restrict bacterial growth by controlling the density of linear ubiquitin chains on the bacterial surface, which serves as a platform for NF-κB activation.Finally, lattice light-sheet microscopy (LLSM) is a newly developed super-resolution microscopy method, which capitalises on previous microscopy techniques (light-sheet microscopy, SIM) and provides gentle and fast super-resolution in a volumetric sample13.
Mutated OTULIN inhibits Ubiquitin. 1 / 1
| 1

reach
Consequently, mutant OTULIN proteins failed to prevent the accumulation of linear Ub chains on target substrates IKK and NEMO, RIPK1, TNFR1, and ASC.
OTULIN increases the amount of Ubiquitin.
| 1
OTULIN increases the amount of Ubiquitin. 1 / 1
| 1

reach
As HOIP associated OTULIN was not recruited to SCs, we next studied whether OTULIN deficiency may increase levels of linear ubiquitin found in the cytosol.
OTULIN decreases the amount of Ubiquitin.
| 1
OTULIN bound to Nsp11 decreases the amount of Ubiquitin. 1 / 1
| 1

reach
OTULIN is upregulated in a PRRSV infection model and interacts with the PRRSV non structural protein 11 (Nsp11) to decrease Ub levels on NEMO and to block NF-kappaB activation and IFN-regulatory transcription factor 3 (IRF3)-mediated type-I IFN production [XREF_BIBR].
OTULIN activates Ubiquitin.
| 1
| 1

reach
Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin dependent and -independent functions.
OTULIN affects TNF
| 3
OTULIN inhibits TNF. 3 / 6
| 3

reach
Concomitant Loss of OTULIN and CYLD Interaction with HOIP Increases M1Ubiquitination at the TNF-RSC and Enhances TNF Induced Gene Activation.

reach
Consistent with the finding that OTULIN overexpression was shown to delay NF-kappaB activation of TNF, whereas its knockdown was reported to increase the output of NF-kappaB signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR], we found that OTULIN overexpression strongly depressed NF-kappaB activity and reduced the release of TNF-alpha, IL-1beta, and IL-6, which are the primary pro inflammatory cytokines that aggravate brain injury.

reach
OTULIN overexpression significantly suppressed the production of TNF-alpha, IL-1beta, and IL-6 in PM and N9 cells via inhibiting the nuclear translocation of NF-kappaB p65 but had no effect on the pro inflammatory cytokines secreted by un activated microglia, which directly indicates that OTULIN suppressed microglia mediated neuroinflammation by inhibiting the NF-kappaB pathway and attenuated the release of inflammatory mediators under the in vitro ischemic condition.
OTULIN affects Glu-Ala
| 6
OTULIN inhibits Glu-Ala.
| 3
| 3

reach
Consistent with our hypothesis, OTULIN silencing reversed the inhibitory effect of EA on the secretion of pro inflammatory factors in the ischaemic cerebral cortex.

reach
EA also enhanced microglial OTULIN expression in the present study, and OTULIN silencing effectively reversed the inhibitory effect of EA on microglial activation, as shown by the increased mean Iba-1 immunofluorescence intensity, which strongly indicates that enhanced OTULIN expression is necessary for EA to alleviate microglial activation.

reach
OTULIN silencing reversed EA suppression of microglial activation after focal cerebral ischaemia and reperfusion injury.
OTULIN activates Glu-Ala.
| 3
| 3

reach
Notably, the silencing of OTULIN obviously reversed the neuroprotective effects of EA, which indicated that OTULIN was involved in the anti-preventive role of EA following acute ischemic stroke.

reach
OTULIN knockdown reversed the neuroprotective effects of EA against ischaemic brain injury.

reach
OTULIN silencing obviously reversed EA neuroprotection, which was demonstrated by worsened neurobehavioural performance, cerebral infarct volume and neuronal injury.
Ubiquitin affects OTULIN
| 5
Ubiquitin inhibits OTULIN.
| 4
| 2

reach
Deficiency of the linear ubiquitin chain-specific deubiquitinase, OTULIN, causes OTULIN-related autoinflammatory syndrome (ORAS), a systemic inflammatory pathology affecting multiple organs including the skin.

reach
Consistently, mutation of the proximal ubiquitin Glu16 to alanine (E16A) reduces the catalytic efficiency (k cat) of OTULIN by 240-fold without significantly affecting binding of the substrate (similar K D and only 3-fold reduction in K M) [XREF_BIBR].
Ubiquitin-G76A inhibits OTULIN. 1 / 1
| 1

reach
As expected, Ub G76A -Ub did not label or inhibit OTULIN and USP5, but it also induced the dose dependent assembly of Ub chains that could be detected with anti-M1-polyUb antibody (XREF_FIG G).
Mutated Ubiquitin inhibits OTULIN. 1 / 1
| 1

reach
Consistently, mutation of ubiquitin Glu16 to Ala reduced the catalytic efficiency of OTULIN by 240-fold without significantly affecting binding of the substrate to the enzyme (similar K d and only a threefold reduction in K m) 29.
Ubiquitin activates OTULIN.
| 1
| 1

reach
Hence, we reveal a mechanism of substrate assisted catalysis in which Glu16 of the proximal Ub activates the catalytic triad of OTULIN by both restricting the movement of the catalytic His339 and introducing a negative charge, presumably for the proper coordination of Asn341 for catalysis.
OTULIN affects IKBKG
| 1 3
OTULIN inhibits IKBKG. 3 / 4
| 1 2

reach
Accordingly, depletion of OTULIN enhanced the recruitment of NEMO to Met1 ubiquitinated RIPK2 in response to L18-MDP, whereas NEMO recruitment was inhibited by OTULIN overexpression.

eidos
OTULIN is upregulated in a PRRSV infection model and interacts with the PRRSV non-structural protein 11 ( Nsp11 ) to decrease Ub levels on NEMO and to block NF-kappaB activation and IFN-regulatory transcription factor 3 ( IRF3 ) - mediated type-I IFN production [ 22 ] .

reach
Overexpression of OTULIN inhibits TNF-alpha-induced NF-kappaB signaling by preventing the association of NEMO with polyubiquitinated RIP1 (Fiil et al., 2013; Keusekotten et al., 2013).
Mutated OTULIN inhibits IKBKG. 1 / 1
| 1

reach
Mutant OTULIN proteins can not restrict the accumulation of Met1 Ub chains on target substrates IKK and NEMO, RIPK1, and ASC.
Tamoxifen affects OTULIN
| 3
| 3

reach
Tamoxifen induced OTULIN deficiency in immune cells led to an acute, serious multi-organ inflammatory phenotype [XREF_BIBR].

reach
Tamoxifen induced Otulin deficiency in immune cells results in an acute severe multiorgan inflammatory phenotype.

reach
Tamoxifen induced Otulin ablation in murine immune cells (CreERT2-OtulinLacZ and flox chimeras) resembles the phenotype described in patients with otulipenia and ORAS including responsiveness to therapy with TNF inhibitors.
UBD affects OTULIN
| 1 2
UBD activates OTULIN. 3 / 3
| 1 2

sparser
More strikingly, we found that OTULIN was directly activated by the bound diubiquitin.

reach
More strikingly, we found that OTULIN was directly activated by the bound diubiquitin.

reach
More strikingly, the structure also revealed that OTULIN is directly activated by the bound diubiquitin : placement of the proximal ubiquitin inserts the ubiquitin side chain of Glu16 directly into the active site of OTULIN, thereby pushing His339 into an active conformation and additionally co-ordinating the third catalytic residue, Asn341 (XREF_FIG).

reach
Increased OTULIN expression was required for EA to inhibit the NF-kappaB signalling pathway in focal cerebral ischaemia and reperfusion rats.

reach
As both CYLD and OTULIN negatively regulate the NF-kappaB signalling cascade, the impact of these deubiquitinases in different LUBAC dependent signalling cascades may be context dependent.

reach
To further investigate whether enhanced OTULIN was required for EA to inhibit the NF-kappaB signalling pathway, OTULIN, p-IkappaBalpha, IkappaBalpha, cytoplasm-p65 and nucleus-p65 proteins from brain tissues in the ischaemic penumbra of the cerebral cortex were detected 24h after reperfusion.
Glu-Ala affects OTULIN
| 3
Glu-Ala increases the amount of OTULIN. 3 / 3
| 3

reach
EA treatment promotes OTULIN gene transcription and protein synthesis in the brain, and enhanced OTULIN expression was primarily located in neurons.

reach
EA enhanced OTULIN expression following focal cerebral ischaemia and reperfusion injury.

reach
EA also enhanced microglial OTULIN expression in the present study, and OTULIN silencing effectively reversed the inhibitory effect of EA on microglial activation, as shown by the increased mean Iba-1 immunofluorescence intensity, which strongly indicates that enhanced OTULIN expression is necessary for EA to alleviate microglial activation.
| 2

reach
OTULIN Tyr 56 phosphorylation is counteracted by the activity of dual-specificity phosphatase 14 (DUSP14), which we identify as an OTULIN phosphatase that limits necroptosis.

reach
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice.
| 1

reach
OTULIN hyper-phosphorylation promotes necroptosis by locking ring finger protein 31 (RNF31, also known as HOIP) away from the cylindromatosis (CYLD) complex, resulting in altered receptor interacting serine/threonine kinase 1 (RIPK1) ubiquitination.
| 1 2
| 1 1

trips
OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.

reach
The OTULIN mediated suppression of hepatocyte apoptosis plays a crucial role in liver pathogeneses, such as hepatitis, fibrosis, and hepatocellular carcinoma [XREF_BIBR].
| 1

reach
OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver.
OTULIN affects Wnt
| 2
OTULIN inhibits Wnt.
| 1
OTULIN inhibits Wnt. 1 / 2
| 1

reach
The interaction of HOIP with OTULIN is also involved in OTULIN suppressing the canonical Wnt signaling pathway activation by LUBAC [XREF_BIBR].
OTULIN activates Wnt.
| 1
OTULIN activates Wnt. 1 / 1
| 1

reach
Thus, OTULIN mediated Wnt and beta-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.
OTULIN affects RNF31
| 2
OTULIN inhibits RNF31.
| 1
OTULIN inhibits RNF31. 1 / 2
| 1

reach
Strikingly, while mice lacking OTULIN in B or Tcells do not display overt inflammatory phenotypes, further analysis indicates that these OTULIN deficient cells have downregulated LUBAC components HOIP and SHARPIN, but not HOIL-1.
OTULIN activates RNF31.
| 1
OTULIN activates RNF31. 1 / 1
| 1

reach
OTULIN hyper-phosphorylation promotes necroptosis by locking ring finger protein 31 (RNF31, also known as HOIP) away from the cylindromatosis (CYLD) complex, resulting in altered receptor interacting serine/threonine kinase 1 (RIPK1) ubiquitination.
OTULIN affects GS26575
| 3
OTULIN inhibits GS26575.
| 2
| 2

reach
OTULIN directly binds the LUBAC component HOIP, and knockdown of OTULIN in human cell lines increases M1 linked chains on LUBAC and its substrates.

reach
The deubiquitinase OTULIN negatively regulates M1 linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN related autoinflammatory syndrome (ORAS) in humans.
OTULIN activates GS26575.
| 1
| 1

reach
While absence of OTULIN induces spontaneous M1 linked polyubiquitination and NF-kappaB activation in myeloid cells, OTULIN deficiency in T and B cells results in loss of LUBAC.
NFkappaB affects OTULIN
| 3
NFkappaB activates OTULIN.
| 2
| 2

reach
NF-kappaB activation and TNF secretion in human OTULIN deficient monocytes.

reach
In line with these observations, TNFalpha stimulation results in reduced Met1 ubiquitination of RIPK1 and NEMO, and decreased NF-kappaB signaling in OTULIN deficient keratinocytes [XREF_BIBR].
NFkappaB increases the amount of OTULIN.
| 1
NFkappaB increases the amount of OTULIN. 1 / 1
| 1

reach
Contrary to this, OTULIN functions to restrict the accumulation of Met1-Ub at basal conditions and early during signaling, and OTULIN expression is not induced by stimulation of NF-kappaB activity.
S1 affects OTULIN
| 3
S1-E314R inhibits OTULIN. 1 / 1
| 1

reach
Point mutations in the S1 (L259E and E314R) or S1 ' (W96A and TQK100-102AAA) Ub binding sites reduced OTULIN activity toward Met1-diUb (XREF_FIG I) by decreasing Met1-diUb affinity (XREF_FIG J).
S1-L259E inhibits OTULIN. 1 / 1
| 1

reach
Point mutations in the S1 (L259E and E314R) or S1 ' (W96A and TQK100-102AAA) Ub binding sites reduced OTULIN activity toward Met1-diUb (XREF_FIG I) by decreasing Met1-diUb affinity (XREF_FIG J).
S1 inhibits OTULIN. 1 / 1
| 1

reach
Point mutations in the S1 (L259E and E314R) or S1 ' (W96A and TQK100-102AAA) Ub binding sites reduced OTULIN activity toward Met1-diUb (XREF_FIG I) by decreasing Met1-diUb affinity (XREF_FIG J).
OTULIN affects OTULIN
| 3
OTULIN activates OTULIN.
| 2
Mutated OTULIN activates OTULIN. 1 / 1
| 1

reach
Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.
OTULIN activates OTULIN. 1 / 1
| 1

reach
This is in stark contrast to the interaction of HOIP with OTULIN, which was substantially increased by OTULIN overexpression (XREF_FIG C).
OTULIN inhibits OTULIN.
| 1
OTULIN-C129A inhibits OTULIN. 1 / 1
| 1

reach
Inactivation of OTULIN by expression of OTULIN C129A in adult mice has recently been reported to cause systemic inflammation, which can be prevented by combined ablation of cell death pathways by deletion of caspase-8, RIPK3 and RIPK1 (Heger etal, 2018).
2 |
Hsa-miR-6849-3p decreases the amount of OTULIN. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
OTULIN affects SNX27
| 2
OTULIN inhibits SNX27. 2 / 2
| 2

reach
However, via association, OTULIN antagonizes SNX27 dependent cargo loading, binding of SNX27 to the VPS26A-retromer subunit and endosome-to-plasma membrane trafficking.

reach
Previous study has shown that OTULIN negatively regulates SNX27 dependent cargo loading [XREF_BIBR].
| PMC
OTULIN affects IL6
| 2
OTULIN inhibits IL6. 2 / 2
| 2

reach
OTULIN overexpression significantly suppressed the production of TNF-alpha, IL-1beta, and IL-6 in PM and N9 cells via inhibiting the nuclear translocation of NF-kappaB p65 but had no effect on the pro inflammatory cytokines secreted by un activated microglia, which directly indicates that OTULIN suppressed microglia mediated neuroinflammation by inhibiting the NF-kappaB pathway and attenuated the release of inflammatory mediators under the in vitro ischemic condition.

reach
Consistent with the finding that OTULIN overexpression was shown to delay NF-kappaB activation of TNF, whereas its knockdown was reported to increase the output of NF-kappaB signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR], we found that OTULIN overexpression strongly depressed NF-kappaB activity and reduced the release of TNF-alpha, IL-1beta, and IL-6, which are the primary pro inflammatory cytokines that aggravate brain injury.
OTULIN affects IL1B
| 2
OTULIN inhibits IL1B. 2 / 2
| 2

reach
OTULIN overexpression significantly suppressed the production of TNF-alpha, IL-1beta, and IL-6 in PM and N9 cells via inhibiting the nuclear translocation of NF-kappaB p65 but had no effect on the pro inflammatory cytokines secreted by un activated microglia, which directly indicates that OTULIN suppressed microglia mediated neuroinflammation by inhibiting the NF-kappaB pathway and attenuated the release of inflammatory mediators under the in vitro ischemic condition.

reach
Consistent with the finding that OTULIN overexpression was shown to delay NF-kappaB activation of TNF, whereas its knockdown was reported to increase the output of NF-kappaB signaling [XREF_BIBR, XREF_BIBR, XREF_BIBR], we found that OTULIN overexpression strongly depressed NF-kappaB activity and reduced the release of TNF-alpha, IL-1beta, and IL-6, which are the primary pro inflammatory cytokines that aggravate brain injury.
SNX27 affects OTULIN
| 2
SNX27 activates OTULIN. 1 / 1
| 1

reach
In this study, we combined immunoprecipitation, immunostaining and cell fractionation assay to show that SNX27 potentiates the localization of OTULIN to TNF receptor complex.
| PMC
SNX27 bound to OTULIN activates OTULIN. 1 / 1
| 1

reach
In summary, we showed that the interaction of SNX27 and OTULIN potentiates the translocation of OTULIN to TNFalpha receptor complex.
| PMC

reach
OTULIN is critical for restraining life threatening spontaneous inflammation, maintaining immune homeostasis and activating NF-kappaB to promote the secretion of pro inflammatory cytokines and restricts bacterial proliferation in infection [XREF_BIBR, XREF_BIBR].

reach
PRRSV infection promotes the expression of the OTULIN gene; in turn, overexpression of OTULIN contributes to PRRSV proliferation.
OTULIN affects Syndrome
| 2
OTULIN inhibits Syndrome.
| 1
| 1

reach
Deficiency of the linear ubiquitin chain-specific deubiquitinase, OTULIN, causes OTULIN-related autoinflammatory syndrome (ORAS), a systemic inflammatory pathology affecting multiple organs including the skin.
OTULIN activates Syndrome.
| 1
Mutated OTULIN activates Syndrome. 1 / 1
| 1

reach
Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.
OTULIN affects PYCARD
| 2
| 1

reach
Only the Otulin treatment reduced high molecular weight ASC, whereas the AMSH treatment had no effect (XREF_FIG).
Mutated OTULIN inhibits PYCARD. 1 / 1
| 1

reach
Mutant OTULIN proteins can not restrict the accumulation of Met1 Ub chains on target substrates IKK and NEMO, RIPK1, and ASC.
OTULIN affects NOD2
| 2
OTULIN inhibits NOD2.
| 1
OTULIN inhibits NOD2. 1 / 1
| 1

reach
Similarly, the recently identified DUB OTULIN XREF_BIBR, XREF_BIBR, XREF_BIBR negatively regulates NOD2 mediated signalling by preventing LUBAC autoubiquitination under basal conditions, as well as restricting the accumulation of linear ubiquitin chains on RIP2 and LUBAC upon stimulation (Fig XREF_FIG).
OTULIN activates NOD2.
| 1
OTULIN activates NOD2. 1 / 1
| 1

reach
Here, we report that OTULIN is critical for limiting Met1-Ub accumulation after nucleotide oligomerization domain containing protein 2 (NOD2) stimulation, and that OTULIN depletion augments signaling downstream of NOD2.
1 |
Valproic acid decreases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Trimellitic anhydride increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Rpain-a affects OTULIN
| 1
| 1

reach
In virus-infected cells, to overcome Otulin-mediated inhibition, RIPA actively degrades Otulin.
1 |

ctd
No evidence text available
1 |
Naphthoquinone increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Ionomycin affects OTULIN
1 |
Ionomycin decreases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
1 |
Hsa-miR-96-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-939-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-766-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6860 decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6771-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6720-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-661 decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6512-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6501-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-616-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-612 decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548t-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548s decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548c-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548ay-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548at-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548as-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548ap-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-548aa decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-5189-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-508-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4696 decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4684-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-451b decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3926 decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-373-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-372-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-371b-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-371a-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3675-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3667-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-32-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3190-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3187-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-29c-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-196a-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-16-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-155-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-1285-3p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-let-7a-5p decreases the amount of OTULIN. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
Hexabromocyclododecane increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
1 |

ctd
No evidence text available
Calcitriol affects OTULIN
1 |
Calcitriol increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
1 |
Bisphenol A decreases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Atrazine affects OTULIN
1 |
Atrazine increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Acrylamide affects OTULIN
1 |
Acrylamide increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
Tobacco Smoke Pollution increases the amount of OTULIN. 1 / 1
1 |

ctd
No evidence text available
TNFRSF1A affects OTULIN
| 1
| 1

reach
While LUBAC appears to be active under basal conditions, Met1-Ub formation on LUBAC components was increased by NOD2 and TNFR1 stimulation in OTULIN depleted cells, suggesting that the propensity of L[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
RNF31 affects OTULIN
| 1
Mutated RNF31 inhibits OTULIN. 1 / 1
| 1

reach
Similarly, mutation of HOIP residues necessary for OTULIN binding prevented OTULIN to exert its inhibitory action on the NF-kappaB pathway.
PIM affects OTULIN
| 1
PIM inhibits OTULIN. 1 / 1
| 1

reach
Importantly, mutation of the cornerstone residue Asn102 to Asp (N102D) or a mutation that affect the hydrophobic PIM pocket (Y82A) reduced the ability of OTULIN to antagonize LUBAC induced NFkappaB activity in comparison to wild-type HOIP (XREF_FIG D).
OTULIN affects rpain-a
| 1
| 1

reach
Ablation of Otulin expression enhanced RIPA and its overexpression inhibited RIPA.
| 1

reach
OTULIN overexpression significantly suppressed the production of TNF-alpha, IL-1beta, and IL-6 in PM and N9 cells via inhibiting the nuclear translocation of NF-kappaB p65 but had no effect on the pro inflammatory cytokines secreted by un activated microglia, which directly indicates that OTULIN suppressed microglia mediated neuroinflammation by inhibiting the NF-kappaB pathway and attenuated the release of inflammatory mediators under the in vitro ischemic condition.
OTULIN affects oraS
| 1
OTULIN activates oraS. 1 / 1
| 1

reach
Mutations in OTULIN have recently been described to cause ORAS, an autosomal recessive autoinflammatory disease (Damgaard etal, 2016; Zhou etal, 2016).

eidos
Therefore , OTULIN downregulates the LUBAC-mediated innate immune responses .

eidos
OTULIN inhibits liver inflammation and hepatocellular carcinoma via restraining FADD - and RIPK1 kinase-mediated hepatocyte apoptosis [ 159 ] .
| 1
| 1

reach
Small interfering RNA (siRNA) against OTULIN resulted in anincrease in LUBAC induced NF-kappaB activation in HEK 293ET and U2OS cells and also in T-REx 293 cells stably expressing a doxycycline inducible OTULIN targeting microRNA (miRNA) (XREF_FIG A and XREF_FIG A-S6C).
OTULIN affects cytokine
| 1
| 1

eidos
Loss of OTULIN expression induces increased cytokine production upon treatment with LPS or staphylococcal enterotoxin B in ex vivo experiments [ 9 ] .
OTULIN affects TSPAN33
| 1
| 1

reach
Taken together, these results indicate that OTULIN overexpression limits the accumulation of microglia in the ischemic penumbra after cerebral ischemia, but this had no effect on the microglial cells in the contralateral cortex.
OTULIN affects TREM2
| 1
Modified OTULIN increases the amount of TREM2. 1 / 1
| 1