Affinage

OTULIN

Ubiquitin thioesterase otulin · UniProt Q96BN8

Length
352 aa
Mass
40.3 kDa
Annotated
2026-06-10
67 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OTULIN (FAM105B) is the mammalian deubiquitinase with absolute specificity for Met1-linked (linear) polyubiquitin, which it hydrolyzes through a substrate-assisted catalytic mechanism in which the proximal ubiquitin activates the protease catalytic triad, as defined by crystal structures of the OTU domain bound to diubiquitin (PMID:23746843). It constitutively associates with the LUBAC E3 ligase by docking a PUB-interacting motif (PIM) onto the HOIP PUB domain, an interaction abolished by phosphorylation of OTULIN Tyr56 (PMID:24726323, PMID:24726327). Through this association OTULIN restrains linear ubiquitin signaling at two levels: it prevents LUBAC auto-ubiquitination to sustain ligase activity (PMID:29950720), and it removes Met1-ubiquitin from receptor-complex substrates including RIPK1/NEMO downstream of TNF (PMID:23746843, PMID:23806334), RIPK2 downstream of NOD2 (PMID:23806334), and ALK1 in BMP9/Smad1/5 signaling (PMID:34157307). OTULIN is essential in vivo: catalytically inactive knock-in mice phenocopy LUBAC deficiency and die mid-gestation from TNFR1- and RIPK1-kinase-dependent cell death rescued by combined caspase-8/RIPK3 loss (PMID:29950720), and tissue-specific loss drives autoinflammation through myeloid NF-κB hyperactivation (PMID:27523608) and epithelial RIPK1-kinase-dependent apoptosis and necroptosis (PMID:32075762, PMID:34625557). A hypomorphic human mutation causes OTULIN-related autoinflammatory syndrome (ORAS), treatable with anti-TNF (PMID:27523608). OTULIN activity is itself tuned by post-translational regulation—ABL1-dependent Tyr56 phosphorylation, TRIM32-mediated non-proteolytic ubiquitination, and LUBAC-dependent linear ubiquitination at Lys64/66—that governs its LUBAC engagement and substrate selection (PMID:31504727, PMID:32770022, PMID:35939695). Beyond the NF-κB axis, OTULIN engages the SNX27-retromer through a C-terminal PDZ-binding motif to control endosomal trafficking independently of catalysis (PMID:31541095, PMID:34315543) and acts on additional substrates including IRF3 and TRAF6 in antiviral signaling (PMID:34545182, PMID:41802043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2013 High

    Establishing how a DUB could be Met1-specific answered why linear ubiquitin signaling has a dedicated eraser, defining OTULIN's catalytic chemistry and chain selectivity.

    Evidence Crystal structure of OTU domain–diubiquitin complex with in vitro DUB assays and Ub Glu16 mutagenesis

    PMID:23746843

    Open questions at the time
    • Did not establish in vivo substrate repertoire
    • Catalytic mechanism shown in vitro, not the cellular regulation of activity
  2. 2013 High

    Linking OTULIN to LUBAC and showing it blocks TNF-induced NEMO–RIPK1 ubiquitin association placed OTULIN as a negative regulator of linear ubiquitin signaling at the receptor complex.

    Evidence Reciprocal Co-IP, overexpression/knockdown, and TNFα stimulation in cells

    PMID:23746843 PMID:23806334

    Open questions at the time
    • Mode of recruitment to the receptor complex not defined
    • Did not resolve whether antagonism is catalytic or stoichiometric
  3. 2013 High

    Identifying RIPK2 as the dominant NOD2-regulated Met1-Ub substrate extended OTULIN's role beyond TNF to a second innate immune receptor pathway.

    Evidence siRNA knockdown, Met1-Ub affinity purification with quantitative MS, NF-κB reporters

    PMID:23806334

    Open questions at the time
    • Did not establish in vivo NOD2 phenotype
    • Spontaneous restriction of LUBAC components not mechanistically separated from receptor signaling
  4. 2014 High

    Defining the HOIP PUB–OTULIN PIM interface and its phospho-regulation by Tyr56 explained how OTULIN is recruited to LUBAC and how that recruitment is switched off.

    Evidence Crystal structure, NMR, Co-IP, phospho-mimetic/null mutagenesis, receptor complex purification

    PMID:24461064 PMID:24726323 PMID:24726327

    Open questions at the time
    • Identity of the Tyr56 kinase not established here
    • Did not address CYLD/SPATA2 competition for the same PUB domain
  5. 2016 High

    Genetic loss-of-function in mice and humans demonstrated OTULIN is non-redundantly required to prevent autoinflammation, with cell-type-specific outcomes on M1-Ub and LUBAC levels.

    Evidence Four conditional knockout mouse models, IP/Western for LUBAC, cytokines, anti-TNF rescue; ORAS patient mutation

    PMID:27523608

    Open questions at the time
    • Did not distinguish whether disease is driven by NF-κB or cell death
    • Mechanism of LUBAC degradation in lymphocytes unresolved
  6. 2018 High

    Catalytic-dead knock-in mice showed OTULIN's DUB activity sustains LUBAC by preventing auto-ubiquitination, placing OTULIN and LUBAC in a single TNFR1/RIPK1-driven cell-death pathway.

    Evidence Catalytic-dead knock-in mice with epistasis (TNFR1-KO, RIPK1-KD, caspase-8-KO, RIPK3-KO), Western for LUBAC auto-ubiquitination

    PMID:29950720

    Open questions at the time
    • Did not identify tissue-specific cell-death effectors beyond embryo
    • Counterintuitive role as LUBAC-promoting rather than purely antagonistic not fully reconciled with receptor-level data
  7. 2019 High

    Discovery of the SNX27-retromer interaction via OTULIN's PDZ-binding motif revealed a catalysis-independent role in endosomal trafficking, broadening OTULIN function beyond NF-κB.

    Evidence MS interactor identification, crystal structure of OTU–PDZ complex, Co-IP, trafficking assays, PDZbm mutagenesis

    PMID:31541095

    Open questions at the time
    • Physiological significance of trafficking role in vivo not established
    • Relationship between trafficking and immune functions unclear
  8. 2019 Medium

    Characterizing caspase-3 cleavage at Asp31 and Tyr56 hyperphosphorylation with DUSP14 as counteracting phosphatase showed OTULIN is dynamically inactivated during cell death.

    Evidence In vitro caspase-3 cleavage, D31A mutagenesis, DUSP14 Co-IP, keratinocyte death assays

    PMID:31825842

    Open questions at the time
    • Single lab; cleavage fragment function not independently confirmed
    • Kinase responsible for necroptotic Tyr56 phosphorylation not identified
  9. 2020 Medium

    Identifying TRIM32-mediated non-proteolytic ubiquitination that blocks OTULIN–HOIP binding added an upstream regulatory layer controlling OTULIN's access to LUBAC.

    Evidence OTULIN complex proteomics, Co-IP, TRIM32 E3-dead mutagenesis, ubiquitination and NF-κB reporter assays

    PMID:31504727

    Open questions at the time
    • Single lab without in vivo validation
    • Ubiquitin chain linkage and exact lysines not fully resolved
  10. 2020 High

    Tissue-specific knockouts dissected the death effectors downstream of OTULIN loss, showing hepatocyte disease is FADD- and RIPK1-kinase-dependent with an mTOR-driven steatohepatitis component.

    Evidence Liver/hepatocyte-specific KO mice with FADD-KO, RIPK1-KD, IFNAR, TNFR1 epistasis; rapamycin rescue; histopathology

    PMID:32075762 PMID:32231246

    Open questions at the time
    • How OTULIN loss drives mTOR activation independent of TNFR1 not defined
    • Relative contribution of apoptosis vs interferon to liver pathology not fully separated
  11. 2020 Medium

    Connecting OTULIN to β-catenin stability and to autophagy via ATG13 extended its substrate range to Wnt signaling and autophagosome maturation.

    Evidence Co-IP, in-cell ubiquitination assays, ABL1 kinase assay, Tyr56 mutants, xenografts; LC3 co-localization and autophagy flux assays

    PMID:32543267 PMID:32770022

    Open questions at the time
    • Single-lab findings without in vivo genetic confirmation
    • Direct vs indirect action on β-catenin and ATG13 ubiquitin not fully resolved
  12. 2021 High

    Demonstrating OTULIN deubiquitinates ALK1, IRF3, TRAF6, and proteasome subunits, and that SNX27 recruits it to the TNF receptor complex, mapped substrate-level mechanisms across vascular, antiviral, and proteostasis pathways.

    Evidence EC-specific KO mice with BMP9/ALK1 rescue, in vitro kinase assays, bio-orthogonal Ub probes, MS site mapping, Co-IP, proteasome activity assays in KO cells

    PMID:34157307 PMID:34315543 PMID:34545182 PMID:34797715

    Open questions at the time
    • Several substrate findings rest on single labs
    • How substrate selectivity is achieved among diverse targets unresolved
  13. 2021 High

    Epidermis- and keratinocyte-specific knockouts established that OTULIN loss in skin drives TNFR1/RIPK1-kinase-dependent necroptosis and apoptosis with type-I IFN and IL-1β signatures.

    Evidence Skin-specific KO mice with RIPK3-KO, MLKL-KO, FADD-KO, RIPK1-KD, TNFR1-KO, MyD88-KO epistasis; scRNA-seq

    PMID:34625556 PMID:34625557

    Open questions at the time
    • Relative weighting of apoptosis vs necroptosis context-dependent
    • Source of MyD88/IL-1 input not pinpointed
  14. 2022 Medium

    Self-deubiquitination/dimerization control and the caveolin-1 haploinsufficiency phenotype refined how OTULIN abundance and LUBAC engagement are maintained and how partial loss manifests differently across cell types.

    Evidence K64/K66 mutagenesis, dimerization/cross-linking assays, in vitro ubiquitination; patient fibroblast caveolin-1 and α-toxin cytotoxicity assays

    PMID:35587511 PMID:35939695

    Open questions at the time
    • Single-lab mechanistic models
    • Link between caveolin-1 accumulation and linear ubiquitin not fully mechanistic
  15. 2023 Medium

    Macrophage and substrate-level studies linked OTULIN loss to RIPK3-driven Nlrp3 inflammasome activation and to STAT3, SCRIB/VANGL2, and SPATA2-dependent LUBAC regulation, expanding its roles into inflammasome biology, stemness, and planar cell polarity.

    Evidence Myeloid-specific KO mice with RIPK3/Nlrp3 epistasis; bio-orthogonal Ub probe for STAT3; interactomics and KO phenotypes for SCRIB/VANGL2; double-KO mice for SPATA2

    PMID:36640323 PMID:36660824 PMID:37589075 PMID:38000038

    Open questions at the time
    • STAT3, SCRIB/VANGL2 roles from single labs
    • Tissue relevance of PCP role not established in vivo
  16. 2024 Medium

    Patient-derived analysis of the dominant-negative Cys129Ser mutation showed catalytic loss impairs LUBAC recruitment to the TNF receptor complex via auto-ubiquitination, mechanistically uniting human disease with the catalytic-dead mouse model.

    Evidence Patient cells, in vitro DUB assay, LUBAC/receptor complex Co-IP, linear-Ub and TNF-induced death assays

    PMID:38630025

    Open questions at the time
    • Single patient-derived study
    • Dominant-negative mechanism not tested in animal model
  17. 2026 Medium

    Mapping OTULIN action on TRAF6 (K104/K142/K371) and OPA1, plus RNF6-mediated OTULIN degradation, extended the LUBAC-OTULIN axis into antiviral amplification, mitochondrial homeostasis, and EMT control.

    Evidence MS site mapping with mutagenesis, MAVS Co-IP, IFN-β reporters, Otulin+/- viral challenge; OPA1/RNF31 Co-IP and knockdown; RNF6 proteomics with proteasome-inhibitor and rescue assays

    PMID:41802043 PMID:42055142 PMID:42218396

    Open questions at the time
    • OPA1 finding low-confidence and single-lab
    • In vivo significance of EMT and mitochondrial roles limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OTULIN achieves substrate and context selectivity—choosing among RIPK1/2, ALK1, IRF3, TRAF6, STAT3, β-catenin, and proteasome subunits in different cell types—and how its many regulatory modifications are integrated remains unresolved.
  • No unifying model for substrate targeting beyond LUBAC association
  • Several substrate and metabolic claims rest on single labs or preprints awaiting confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 7 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0016787 hydrolase activity 1
Localization
GO:0005768 endosome 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 2
Partners
ABL1DUSP14RNF31RNF6SCRIBSNX27SPATA2TRIM32
Complex memberships
LUBACSNX27-retromer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 OTULIN (FAM105B) is a deubiquitinase with exquisite specificity for Met1-linked (linear) polyubiquitin chains; crystal structures of the OTULIN catalytic domain in complex with diubiquitin revealed Met1-specific ubiquitin-binding sites and a mechanism of substrate-assisted catalysis in which the proximal ubiquitin activates the catalytic triad of the protease. Mutation of Ub Glu16 reduces OTULIN kcat 240-fold. Crystal structure of OTU catalytic domain–diubiquitin complex; in vitro DUB activity assays; site-directed mutagenesis of Ub Glu16 Cell High 23746843
2013 OTULIN binds LUBAC and overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1, demonstrating that OTULIN antagonizes LUBAC-mediated linear ubiquitin signaling at the receptor complex level. Co-immunoprecipitation; overexpression and knockdown in cells; TNFα stimulation assays monitoring NEMO–RIPK1 ubiquitin association Cell High 23746843 23806334
2013 OTULIN depletion augments NF-κB signaling downstream of NOD2, and affinity purification of Met1-ubiquitin followed by quantitative proteomics identified RIPK2 as the predominant NOD2-regulated Met1-ubiquitin substrate; OTULIN restricts Met1-Ub on RIPK2 and on LUBAC components spontaneously. siRNA knockdown; affinity purification of Met1-Ub chains coupled to quantitative mass spectrometry; immunoprecipitation; NF-κB reporter assays Molecular cell High 23806334
2014 OTULIN binds LUBAC via a conserved PUB-interacting motif (PIM) that docks onto the PUB domain of HOIP; crystal structures and NMR revealed the molecular basis of the high-affinity interaction. Phosphorylation of OTULIN Tyr56 within the PIM prevents HOIP binding, whereas unphosphorylated OTULIN is part of the endogenous LUBAC complex. Crystal structure of HOIP PUB–OTULIN PIM complex; NMR; Co-immunoprecipitation; phospho-mimetic/phospho-null mutagenesis; in vitro binding assays Molecular cell High 24726323 24726327
2014 OTULIN must be present on LUBAC (via HOIP PUB–PIM interaction) to restrict Met1-polyUb signaling; HOIP binding is required for recruitment of OTULIN to the TNF receptor complex to counteract HOIP-dependent NF-κB activation. NF-κB luciferase reporter assays; Co-immunoprecipitation; site-directed mutagenesis of OTULIN Tyr56 and HOIP PUB; TNF receptor complex purification Molecular cell High 24726323 24726327
2014 Both CYLD and OTULIN interact with LUBAC via the PUB domain of HOIP even in unstimulated cells, and their interaction with HOIP synergistically suppresses LUBAC-mediated linear polyubiquitination and NF-κB activation; OTULIN interaction with HOIP also suppresses canonical Wnt signaling activation by LUBAC. Co-immunoprecipitation; cell-free translation/binding assays; NF-κB reporter assays; HOIP-null cell reconstitution with binding-deficient HOIP mutants Genes to cells Medium 24461064
2016 OTULIN is essential in vivo for preventing spontaneous M1-linked polyubiquitin accumulation and NF-κB activation in myeloid cells; OTULIN deficiency in B and T cells instead causes LUBAC degradation and downregulation of M1-polyUb signaling. A hypomorphic human OTULIN mutation causes OTULIN-related autoinflammatory syndrome (ORAS) treatable by anti-TNF. Four independent conditional OTULIN knockout mouse models; immunoprecipitation; Western blot for LUBAC levels; cytokine measurements; anti-TNF rescue experiments Cell High 27523608
2018 OTULIN promotes LUBAC activity by preventing LUBAC auto-ubiquitination with linear polyubiquitin; catalytically inactive OTULIN knock-in mice resemble LUBAC-deficient mice and die midgestation from TNFR1- and RIPK1-kinase-dependent cell death. Embryonic lethality is rescued by combined loss of caspase-8 and RIPK3, showing OTULIN and LUBAC function in a linear pathway. Catalytic-dead OTULIN knock-in mice (constitutive and endothelial-specific); genetic epistasis with TNFR1-KO, RIPK1-kinase-dead KI, caspase-8-KO, RIPK3-KO; Western blot for LUBAC auto-ubiquitination Nature High 29950720
2019 OTULIN interacts with SNX27 (sorting nexin 27) via its C-terminal PDZ-binding motif (PDZbm) engaging the cargo-binding PDZ domain of SNX27; a second interface between the OTULIN OTU domain and the SNX27 PDZ domain was revealed by crystal structure. Via this association, OTULIN antagonizes SNX27-dependent cargo loading and VPS26A-retromer binding, inhibiting endosome-to-plasma membrane trafficking in a catalysis-independent manner. Mass spectrometry identification of OTULIN interactor; crystal structure of OTU domain–PDZ domain complex; Co-immunoprecipitation; endosomal trafficking assays; mutagenesis of PDZbm Nature communications High 31541095
2019 OTULIN is cleaved by caspase-3 at Asp-31 during apoptosis, generating a C-terminal fragment that restricts caspase activation and cell death. During necroptosis, OTULIN is hyper-phosphorylated at Tyr-56, which modulates RIPK1 ubiquitin dynamics and promotes cell death; this phosphorylation is counteracted by the phosphatase DUSP14, identified as an OTULIN phosphatase. In vitro caspase-3 cleavage assay; site-directed mutagenesis (D31A); Co-immunoprecipitation of DUSP14; phosphorylation assays; keratinocyte apoptosis/necroptosis induction assays Cell reports Medium 31825842
2020 TRIM32 interacts with OTULIN and conjugates non-proteolytic (K48/K63-linked) polyubiquitin chains onto OTULIN, which blocks the OTULIN–HOIP interaction, thereby preventing OTULIN from suppressing LUBAC and promoting NF-κB activation. TRIM32 E3 ligase activity is required for this effect. Proteomics of OTULIN protein complex; Co-immunoprecipitation; TRIM32 E3 ligase domain mutagenesis; ubiquitination assay; NF-κB reporter assay; genetic complementation Journal of molecular cell biology Medium 31504727
2020 OTULIN deficiency in liver parenchymal cells triggers steatohepatitis via aberrant mTOR activation (independent of TNFR1 signaling); rapamycin administration significantly reduces liver pathology in hepatocyte-specific OTULIN-KO mice. Liver-specific OTULIN knockout mice; TNFR1-KO epistasis; mTOR pathway Western blot; rapamycin pharmacological rescue; histopathology Cell death and differentiation Medium 32231246
2020 OTULIN deficiency in hepatocytes causes apoptosis through FADD-dependent and RIPK1-kinase-dependent pathways; genetic ablation of FADD completely rescues, and RIPK1 kinase-dead knockin significantly protects, mice from OTULIN-deficient liver disease. Type I interferons also contribute to disease in this model. Hepatocyte-specific OTULIN-KO mice; genetic epistasis with FADD-KO and RIPK1 kinase-dead KI; IFNAR epistasis; histopathology; TUNEL assays Cell reports High 32075762
2020 OTULIN inhibits linear ubiquitination of β-catenin, preventing its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association between OTULIN and β-catenin is enhanced by ABL1-dependent phosphorylation of OTULIN Tyr56, which is triggered by genotoxic stress. Co-immunoprecipitation; in-cell ubiquitination assay; proteasome inhibition; ABL1 kinase assay; phospho-mimetic/null OTULIN Tyr56 mutants; xenograft tumor models Nature communications Medium 32770022
2020 LUBAC and OTULIN localize to the phagophore area; LUBAC component RNF31 translocates to LC3 puncta upon autophagy induction. OTULIN knockdown promotes autophagy initiation but blocks autophagosome maturation by causing excessive linear-ubiquitinated ATG13 accumulation at the phagophore. siRNA knockdown; confocal immunofluorescence co-localization with LC3; autophagy flux assays (GFP-RFP-LC3); Western blot for ATG13 ubiquitination Autophagy Medium 32543267
2021 OTULIN deubiquitinates ALK1 (Activin receptor-like kinase 1) to remove linear ubiquitin chains conjugated by LUBAC; linear ubiquitination of ALK1 inhibits its kinase activity and Smad1/5 activation. EC-specific or constitutive Otulin deletion causes arteriovenous malformations and embryonic lethality rescued by BMP9 pretreatment or constitutively active ALK1 knockin. EC-specific and constitutive Otulin-KO mice; in vitro ALK1 kinase assay with/without linear ubiquitination; Smad1/5 phosphorylation Western blot; Co-immunoprecipitation; ALK1Q200D knockin rescue; HOIP inhibitor treatment of HHT2 patient-derived ECs Molecular cell High 34157307
2021 SNX27 recruits OTULIN to the membrane-associated TNF receptor complex via their PDZ interaction; OTULIN deubiquitinates linear polyubiquitin at the TNF receptor complex, and chemical inhibition of SNX27-retromer translocation blocks OTULIN membrane localization and enhances TNFα-induced NF-κB signaling. Co-immunoprecipitation; TNF receptor complex purification; cholera toxin pharmacological inhibition; confocal imaging; NF-κB reporter assay Cell & bioscience Medium 34315543
2021 OTULIN deficiency in epidermis-specific KO mice causes TNFR1-dependent, RIPK1-kinase-activity-dependent keratinocyte death that is primarily necroptosis (requiring RIPK3/MLKL); combined loss of RIPK3 and FADD fully prevents skin lesions, indicating redundant roles of apoptosis and necroptosis. MyD88 deficiency suppresses skin inflammation, implicating TLR/IL-1 signaling. Epidermis-specific OTULIN KO mice; genetic epistasis with RIPK3-KO, MLKL-KO, FADD-KO, RIPK1 kinase-dead KI, TNFR1-KO, MyD88-KO; histopathology Nature communications High 34625557
2021 Keratinocyte-specific OTULIN ablation causes inflammatory skin lesions driven by keratinocyte cell death; genetic deletion of Tnfr1, RIPK1 kinase-dead KI, or combined keratinocyte-specific deletion of FADD and MLKL completely rescues dermatitis. OTULIN-deficient keratinocytes display a type-I interferon and IL-1β response signature. Keratinocyte-specific OTULIN KO mice; genetic epistasis with Tnfr1-KO, Ripk1-KD KI, FADD/MLKL double KO; single-cell RNA-sequencing; cytokine inhibition Nature communications High 34625556
2021 OTULIN deubiquitinates IRF3 to remove linear polyubiquitin chains, inhibiting RIPA (RIG-I-induced pathway of apoptosis). During virus infection, RIPA overcomes OTULIN inhibition by caspase-3 cleavage of OTULIN at D31 followed by proteasomal degradation of the cleaved fragment, preceded by K48-linked ubiquitination at K64 and K197 by HOIP. OTULIN overexpression/knockdown; caspase-3 in vitro cleavage assay; D31A/K64R/K197R mutagenesis; mass spectrometry identification of ubiquitination sites; Co-immunoprecipitation with LUBAC/HOIP; virus infection apoptosis assay Cell death and differentiation Medium 34545182
2021 OTULIN deubiquitinates proteasome subunits; OTULIN deficiency causes proteasome dysregulation in cells, which is the mechanistic basis for elevated type I interferon signaling in OTULIN-deficient patients and cell lines. CRISPR-generated OTULIN-KO cell lines; proteasome activity assays; Co-immunoprecipitation of proteasome subunits with OTULIN; type I IFN pathway assays in patient PBMCs/monocytes Science advances Medium 34797715
2022 OTULIN undergoes self-deubiquitination intermolecularly via dimerization; Lys64/66 of OTULIN are linearly ubiquitinated in a LUBAC-dependent manner to maintain OTULIN–LUBAC interaction under unstressed conditions. Genotoxic stress induces OTULIN dimerization (via cysteine-mediated disulfide bonds under oxidative stress) and self-deubiquitination, leading to OTULIN–LUBAC dissociation and NF-κB overactivation. Mutagenesis of OTULIN K64/K66; Co-immunoprecipitation; in vitro ubiquitination assay; cross-linking/dimerization assays; genotoxic stress and oxidative stress treatments PNAS Medium 35939695
2022 OTULIN haploinsufficiency causes accumulation of caveolin-1 in dermal fibroblasts (but not leukocytes), which facilitates cytotoxic damage by staphylococcal α-toxin; TNFR-mediated NF-κB signaling remains intact in haploinsufficient fibroblasts. Patient-derived fibroblast studies; linear ubiquitin accumulation assay; caveolin-1 protein level measurement; α-toxin cytotoxicity assay; leukocyte phenotyping Science Medium 35587511
2023 OTULIN deficiency in macrophages licenses RIPK3-mediated cell death, which activates the Nlrp3 inflammasome independently of gasdermin D-mediated pyroptosis, leading to RIPK3-dependent IL-1β secretion; elevated serum IL-1β in myeloid-specific OTULIN-KO mice is abolished by Ripk3 or Nlrp3 deletion. Myeloid-specific OTULIN KO mice; genetic epistasis with RIPK3-KO and Nlrp3-KO; gasdermin D knockdown; IL-1β ELISA; macrophage cell death assays Science immunology High 38000038
2023 OTULIN interacts with SCRIB via its C-terminal PDZ-binding motif; Met1-Ub chains associate with VANGL2 and PRICKLE1 but not SCRIB, directing VANGL2 surface presentation. OTULIN is recruited to VANGL2-enriched cell-cell contacts and its loss causes deficits in Wnt5a-induced filopodia extension and VANGL2 trafficking, implicating linear (de)ubiquitination in planar cell polarity signaling. HEK293 cell-based interactomic analysis; Co-immunoprecipitation; confocal imaging of OTULIN at cell-cell contacts; OTULIN-KO cells; Wnt5a-stimulated filopodia assay; VANGL2-GFP trafficking assay Disease models & mechanisms Medium 37589075
2023 STAT3 is a direct substrate of linear ubiquitination in glioblastoma stem-like cells; linear ubiquitination of STAT3 negatively regulates its activity by recruiting the phosphatase TC-PTP to STAT3. Preferential OTULIN expression in GSCs deubiquitinates STAT3 to drive persistent STAT3 signaling and maintain stemness. Bio-orthogonal linear ubiquitin probe (NAEK-Ub) for substrate identification; Co-immunoprecipitation; STAT3 activity assays; OTULIN knockdown in GSCs; TC-PTP recruitment assay Nucleic acids research Medium 36660824
2023 SPATA2 competes with OTULIN for binding to HOIP via its PUB-interacting motif (PIM) and zinc finger domain, thereby promoting LUBAC auto-ubiquitination. Cyld-/-Spata2-/- double mutant mice show perinatal lethality and elevated M1-linked ubiquitination dependent on OTULIN, indicating SPATA2 counteracts OTULIN-mediated LUBAC deubiquitination independently of CYLD. Cyld-/-, Spata2-/-, and Cyld-/-Spata2-/- double KO mice; competitive binding assays (Co-IP with PIM mutants); M1-Ub Western blot; genetic rescue by additional OTULIN deletion Cell reports Medium 36640323
2024 The dominant-negative OTULIN Cys129Ser mutation ablates deubiquitinase activity without affecting protein stability or LUBAC/linear-ubiquitin binding; loss of catalytic activity causes LUBAC auto-ubiquitination that impairs LUBAC recruitment to the TNF receptor signaling complex, promoting TNF-induced cell death. Patient-derived cell studies; in vitro DUB activity assay; Co-immunoprecipitation of LUBAC with TNF receptor complex; linear ubiquitin accumulation assay; TNF-induced cell death assay Journal of experimental medicine Medium 38630025
2024 OTULIN prevents GPX4 proteasomal degradation by reducing its ubiquitin level (linear deubiquitination of GPX4), thereby conferring resistance to cisplatin-induced mitochondrial apoptosis (not ferroptosis) in osteosarcoma cells. OTULIN overexpression/knockdown; GPX4 ubiquitination assay; proteasome inhibitor (MG132) rescue; cell death assays (apoptosis vs ferroptosis markers); xenograft model Journal of experimental & clinical cancer research Low 39721999
2025 OTULIN regulates the ubiquitination of NCOA4, preventing its degradation and thereby enabling NCOA4-mediated FTH1 accumulation; this protects hepatocytes from APAP-induced ferroptosis by maintaining iron homeostasis. OTULIN stable cell lines; ubiquitination assay of NCOA4; Co-immunoprecipitation; ferroptosis markers (GSH, lipid peroxidation); mouse APAP injury model International immunopharmacology Low 40158433
2026 OTULIN removes linear ubiquitin chains from TRAF6 at K104, K142, and K371 to suppress RIG-I-dependent antiviral signaling; linear ubiquitination of TRAF6 by LUBAC promotes K63-linked ubiquitination of TRAF6 and strengthens its association with MAVS to amplify antiviral responses. OTULIN-KO mice exhibit enhanced antiviral immunity. OTULIN overexpression/knockout in HeLa and iBMDM cells; lentiviral reconstitution; TRAF6 ubiquitination mass spectrometry; K104R/K142R/K371R mutagenesis; MAVS Co-immunoprecipitation; IFN-β reporter assay; Otulin+/- mouse viral challenge PNAS Medium 41802043
2025 OTULIN interacts with AMPK, controls its M1-ubiquitination, and restricts AMPK activation in response to glucose starvation and allosteric activation; LUBAC promotes AMPK activation while OTULIN restricts it, placing the LUBAC-OTULIN axis as a regulator of metabolic signaling. LUBAC and OTULIN KO/KD cells; AMPK activity assays; Co-immunoprecipitation of OTULIN with AMPK; M1-ubiquitination assay of AMPK; metabolic flux measurements; Drosophila starvation survival (LUBAC-deficient) bioRxivpreprint Low bio_10.1101_2024.11.08.622598
2025 In OTULIN-deficient keratinocytes, β-catenin accumulates linear ubiquitin chains promoting its K48-linked ubiquitination and proteasomal degradation, reducing Wnt/β-catenin signaling and causing TCF3 degradation; restoring β-catenin stabilization prevents progressive skin inflammation and keratinocyte death. Keratinocyte-specific OTULIN KO mice; β-catenin linear ubiquitination assay; TCF3 protein level assay; β-catenin stabilizing genetic/pharmacological interventions; skin inflammation rescue assays bioRxivpreprint Low bio_10.1101_2025.01.08.631848
2026 RNF6 E3 ligase ubiquitinates OTULIN and promotes its degradation; RNF6 knockdown prevents OTULIN ubiquitination/degradation and thereby suppresses TGF-β1-induced epithelial-mesenchymal transition in bronchial epithelial cells. Silencing RNF6 phenocopies OTULIN overexpression in blocking partial EMT. Label-free proteomics combined with Co-IP/mass spectrometry; Co-IP validation; cycloheximide and MG132 assays for protein stability; OTULIN overexpression rescue of RNF6 knockdown; EMT marker Western blot Biochemical pharmacology Medium 42055142
2026 OTULIN directly interacts with mitochondrial fusion protein OPA1 and regulates its ubiquitination status; the E3 ligase RNF31/HOIP ubiquitinates OPA1, and OTULIN counteracts RNF31-mediated OPA1 destabilization, thereby maintaining mitochondrial homeostasis in alveolar epithelial cells under hyperoxic stress. Co-immunoprecipitation of OTULIN with OPA1; RNF31 knockdown and OTULIN overexpression/knockdown in alveolar epithelial cells; OPA1 ubiquitination assay; mitochondrial ROS and membrane potential measurements; hyperoxia neonatal mouse model Cellular & molecular biology letters Low 42218396

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 407 23746843
2016 The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell 277 27523608
2017 CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell death and differentiation 221 28362430
2013 OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Molecular cell 218 23806334
2018 OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature 181 29950720
2014 Molecular basis and regulation of OTULIN-LUBAC interaction. Molecular cell 163 24726323
2014 Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling. Molecular cell 153 24726327
2014 Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. Genes to cells : devoted to molecular & cellular mechanisms 105 24461064
2019 OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO molecular medicine 98 30804083
2021 Exosomal OTULIN from M2 macrophages promotes the recovery of spinal cord injuries via stimulating Wnt/β-catenin pathway-mediated vascular regeneration. Acta biomaterialia 79 34551329
2020 OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer. Cell death and differentiation 70 32231246
2020 LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13. Autophagy 69 32543267
2020 ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers. Nature communications 60 32770022
2018 Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-κB signaling pathway in cerebral ischemia/reperfusion rats. Journal of neuroinflammation 57 29544517
2022 Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Science (New York, N.Y.) 56 35587511
2020 OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis. Cell reports 50 32075762
2021 OTULIN in NF-κB signaling, cell death, and disease. Trends in immunology 48 34074601
2021 OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice. Nature communications 45 34625557
2019 Regulation of the endosomal SNX27-retromer by OTULIN. Nature communications 43 31541095
2019 Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death. Cell reports 42 31825842
2021 OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. Nature communications 33 34625556
2022 Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS. EMBO molecular medicine 31 35170849
2020 Ubiquitin-dependent and -independent functions of OTULIN in cell fate control and beyond. Cell death and differentiation 31 33288901
2017 A Linear Diubiquitin-Based Probe for Efficient and Selective Detection of the Deubiquitinating Enzyme OTULIN. Cell chemical biology 31 28919039
2021 OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin. Molecular cell 29 34157307
2018 The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV. Journal of virology 29 29444948
2021 Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production. Science advances 28 34797715
2015 Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN. The FEBS journal 27 26503766
2020 Non-proteolytic ubiquitination of OTULIN regulates NF-κB signaling pathway. Journal of molecular cell biology 26 31504727
2021 OTULIN is a new target of EA treatment in the alleviation of brain injury and glial cell activation via suppression of the NF-κB signalling pathway in acute ischaemic stroke rats. Molecular medicine (Cambridge, Mass.) 23 33836646
2021 The antiviral action of the RIG-I induced pathway of apoptosis (RIPA) is enhanced by its ability to degrade Otulin, which deubiquitinates IRF3. Cell death and differentiation 18 34545182
2024 Dominant negative OTULIN-related autoinflammatory syndrome. The Journal of experimental medicine 17 38630025
2024 A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome. The Journal of experimental medicine 14 38652464
2023 A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma. Nucleic acids research 14 36660824
2022 Reciprocal interplay between OTULIN-LUBAC determines genotoxic and inflammatory NF-κB signal responses. Proceedings of the National Academy of Sciences of the United States of America 14 35939695
2016 OTULIN deficiency causes auto-inflammatory syndrome. Cell research 14 27686184
2023 Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion. Science immunology 13 38000038
2021 SNX27-driven membrane localisation of OTULIN antagonises linear ubiquitination and NF-κB signalling activation. Cell & bioscience 12 34315543
2023 OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection. Cell death & disease 10 37598207
2023 OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition. Journal of clinical immunology 10 38129331
2024 OTULIN confers cisplatin resistance in osteosarcoma by mediating GPX4 protein homeostasis to evade the mitochondrial apoptotic pathway. Journal of experimental & clinical cancer research : CR 9 39721999
2024 OTULIN-related conditions: Report of a new case and review of the literature using GenIA. Clinical immunology (Orlando, Fla.) 8 38914362
2024 OTULIN's influence on neuroinflammation and pain modulation in trigeminal neuralgia. CNS neuroscience & therapeutics 8 39169794
2024 The Effect of Thymoquinone on the TNF-α/OTULIN/NF-κB Axis Against Cisplatin-İnduced Testicular Tissue Damage. Reproductive sciences (Thousand Oaks, Calif.) 7 38658488
2020 OTULIN couples WNT signaling to resistance in triple-negative breast cancer. Molecular & cellular oncology 7 33241111
2024 Downregulation of otulin induces inflammasome activation in neutrophilic asthma. The Journal of allergy and clinical immunology 6 38599290
2021 Global Screening of LUBAC and OTULIN Interacting Proteins by Human Proteome Microarray. Frontiers in cell and developmental biology 6 34262903
2025 OTULIN orchestrates NCOA4-FTH1 complex to alleviate APAP-induced hepatocyte Ferroptosis. International immunopharmacology 5 40158433
2023 SPATA2 restricts OTULIN-dependent LUBAC activity independently of CYLD. Cell reports 5 36640323
2024 OTULIN Can Improve Spinal Cord Injury by the NF-κB and Wnt/β-Catenin Signaling Pathways. Molecular neurobiology 4 38561559
2024 OTULIN of exosomes derived from Schwann cells promotes peripheral nerve injury repair by regulating macrophage polarization via deubiquitination of ERBB2. Neuroscience letters 4 38723761
2024 OTULIN deficiency: focus on innate immune system impairment. Frontiers in immunology 4 38774872
2024 OTULIN haploinsufficiency predisposes to environmentally directed inflammation. Frontiers in immunology 4 38827742
2020 Human induced pluripotent stem cells generated from a patient with a homozygous L272P mutation in the OTULIN gene (NIHTVBi014-A). Stem cell research 4 32721894
2023 Integrated Single-Cell and Transcriptome Sequencing Analyses Develop a Ubiquitination-Associated Signature in Gastric Cancer and Identified OTULIN as a Novel Biomarker. Frontiers in bioscience (Landmark edition) 2 38062820
2022 Screening of OTULIN gene mutation with targeted next generation sequencing in Turkish populations and in silico analysis of these mutations. Molecular biology reports 2 35294702
2025 Upregulation of OTULIN Alleviated Recurrent Pregnancy Loss by Suppressing Trophoblast Dysfunction and NF-κB Signaling Pathway. Molecular reproduction and development 1 40372975
2025 The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons. Genomic psychiatry : advancing science from genes to society 1 41799830
2024 OTULIN-related conditions: Report of a new case and review of the literature using GenIA. Research square 1 38712244
2023 An interaction between OTULIN and SCRIB uncovers roles for linear ubiquitination in planar cell polarity. Disease models & mechanisms 1 37589075
2026 Deubiquitinase OTULIN dampens RIG-I-dependent antiviral signaling by removing linear ubiquitination from TRAF6. Proceedings of the National Academy of Sciences of the United States of America 0 41802043
2026 Regulation of OTULIN ubiquitination by RNF6 alleviates asthma via mitigating epithelial-mesenchymal transition‑like phenotypic changes. Biochemical pharmacology 0 42055142
2026 OTULIN protects hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31. Cellular & molecular biology letters 0 42218396
2026 Association of peripheral blood LUBAC and OTULIN expression with severity and outcome in acute ischemic stroke: a prospective cohort study. Frontiers in immunology 0 42245667
2025 OTULIN Interactome Reveals Immune Response and Autophagy Associated with Tauopathy in a Mouse Model. bioRxiv : the preprint server for biology 0 39974971
2025 FAM105B Promotes Hepatocellular Carcinoma Progression and Metastasis by Activating the PI3K/AKT/MTOR Signaling Pathway and Inducing Epithelial-Mesenchymal Transition. Journal of hepatocellular carcinoma 0 40726617
2020 The plot thickens: OTULIN regulation in cell death. Molecular & cellular oncology 0 32944611

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