Affinage

OTULIN

Ubiquitin thioesterase otulin · UniProt Q96BN8

Length
352 aa
Mass
40.3 kDa
Annotated
2026-04-29
64 papers in source corpus 33 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OTULIN is the sole mammalian deubiquitinase with absolute specificity for Met1 (linear)-linked polyubiquitin chains, functioning as a master regulator of linear ubiquitin signaling across NF-κB, cell death, Wnt/β-catenin, autophagy, type I interferon, and angiogenic pathways. It constitutively associates with the LUBAC E3 ligase complex via a PIM–HOIP PUB domain interaction—regulated by ABL1-mediated Tyr56 phosphorylation, DUSP14-mediated dephosphorylation, TRIM32-mediated ubiquitination, and stress-induced dimerization—where it counteracts LUBAC auto-ubiquitination to maintain LUBAC competence for TNF receptor signaling complex recruitment, and removes linear ubiquitin from substrates including RIPK1, RIPK2, NEMO, IRF3, TRAF6, STAT3, ALK1, ATG13, β-catenin, and proteasome subunits (PMID:23746843, PMID:24726323, PMID:29950720, PMID:34157307, PMID:41802043). Loss of OTULIN catalytic activity in vivo causes TNFR1/RIPK1-kinase-dependent apoptosis and RIPK3/MLKL-dependent necroptosis in a cell-type-specific manner, driving lethal embryonic phenotypes, systemic autoinflammation, steatohepatitis, and skin lesions rescued by genetic ablation of cell death effectors (PMID:27523608, PMID:29950720, PMID:32075762, PMID:34625557, PMID:38000038). Biallelic loss-of-function mutations in OTULIN cause OTULIN-related autoinflammatory syndrome (ORAS), characterized by systemic inflammation, and haploinsufficiency renders dermal fibroblasts susceptible to staphylococcal α-toxin via caveolin-1 accumulation (PMID:30804083, PMID:35587511).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2013 High

    Establishing that OTULIN is the dedicated Met1-linked polyubiquitin deubiquitinase resolved the question of which enzyme opposes LUBAC-generated linear chains, and the crystal structure revealed a unique substrate-assisted catalytic mechanism where proximal ubiquitin Glu16 activates the catalytic triad.

    Evidence Crystal structures of OTULIN OTU domain with Met1-diubiquitin, in vitro DUB assays with chain-linkage specificity panels, and Glu16 mutagenesis reducing kcat 240-fold

    PMID:23746843 PMID:23806334

    Open questions at the time
    • Full-length OTULIN structure not determined
    • Processivity mechanism on longer chains not resolved
    • Whether OTULIN acts as monomer or dimer in vivo was unknown
  2. 2014 High

    Defining the structural basis of the OTULIN–HOIP PUB domain interaction via the PIM motif and demonstrating that Tyr56 phosphorylation disrupts this binding established how OTULIN is recruited to LUBAC and how its association is dynamically regulated.

    Evidence Crystal structures and NMR of OTULIN PIM–HOIP PUB complex, phosphomimetic Y56E mutagenesis abolishing binding, endogenous complex analysis

    PMID:24461064 PMID:24726323 PMID:24726327

    Open questions at the time
    • Identity of the kinase phosphorylating Tyr56 under physiological conditions was not yet known
    • Stoichiometry of OTULIN within the endogenous LUBAC complex not determined
  3. 2016 High

    In vivo mouse knockouts demonstrated that OTULIN is essential for preventing TNF-driven systemic inflammation, with cell-type-specific outcomes: myeloid OTULIN loss causes spontaneous NF-κB activation and linear Ub accumulation, while lymphocyte loss causes LUBAC degradation.

    Evidence Four independent conditional and constitutive OTULIN knockout mouse models, anti-TNF rescue, cell-type-specific biochemistry

    PMID:27523608

    Open questions at the time
    • Why myeloid and lymphoid cells show opposite LUBAC stability outcomes was unexplained
    • Downstream cell death pathways not genetically dissected
  4. 2018 High

    Catalytic-inactive OTULIN knock-in mice phenocopied LUBAC deficiency with midgestational lethality, proving OTULIN promotes LUBAC function by preventing auto-ubiquitination, and genetic rescue by caspase-8/RIPK3 double deletion established that OTULIN prevents TNFR1/RIPK1-kinase-dependent apoptosis and necroptosis.

    Evidence OTULIN C129A knock-in mice, LUBAC auto-ubiquitination biochemistry, caspase-8/RIPK3 double-KO and RIPK1 kinase-dead epistasis rescues

    PMID:29950720

    Open questions at the time
    • Whether OTULIN catalytic activity has LUBAC-independent essential functions in embryogenesis
    • Tissue-specific contributions to embryonic lethality not mapped
  5. 2019 High

    Discovery of a non-catalytic function: OTULIN binds SNX27 via a C-terminal PDZ-binding motif and antagonizes SNX27-dependent endosome-to-plasma membrane cargo trafficking, expanding OTULIN's roles beyond deubiquitination.

    Evidence MS interactome, crystal structure of OTU–SNX27 PDZ complex, endosomal trafficking functional assays, mutagenesis

    PMID:31541095

    Open questions at the time
    • Physiological substrates whose trafficking is controlled by OTULIN–SNX27 not fully catalogued
    • In vivo significance of the non-catalytic function not tested
  6. 2019 Medium

    OTULIN is post-translationally regulated during cell death: caspase-3 cleaves OTULIN at Asp-31 during apoptosis generating a death-restricting fragment, while Tyr56 hyper-phosphorylation during necroptosis modulates RIPK1 ubiquitin dynamics; DUSP14 was identified as the phosphatase reversing Tyr56 phosphorylation.

    Evidence D31A mutagenesis in apoptosis assays, necroptosis assays with phospho-mutants, biochemical identification of DUSP14

    PMID:31825842

    Open questions at the time
    • Kinase responsible for Tyr56 phosphorylation in necroptosis not identified in this study
    • In vivo relevance of caspase-3 cleavage not tested genetically
  7. 2020 High

    Multiple new substrates and signaling axes were identified: ABL1 phosphorylates OTULIN Tyr56 to promote β-catenin deubiquitination and Wnt signaling upon DNA damage; OTULIN/LUBAC regulate autophagy via ATG13 linear ubiquitination; TRIM32 ubiquitinates OTULIN to displace it from HOIP and activate NF-κB; and hepatocyte-specific OTULIN loss triggers FADD/RIPK1-dependent apoptosis and mTOR-driven steatohepatitis.

    Evidence ABL1 kinase assays with xenograft models; siRNA knockdown with autophagy flux assays; TRIM32 MS/genetic complementation; liver-specific KO with FADD KO and RIPK1-KD epistasis, rapamycin rescue

    PMID:31504727 PMID:32075762 PMID:32231246 PMID:32543267 PMID:32770022

    Open questions at the time
    • Whether ABL1-Tyr56 phosphorylation promotes β-catenin binding or catalytic activity or both not fully resolved
    • How OTULIN loss activates mTOR independently of TNFR1 is mechanistically unclear
    • Whether TRIM32-mediated regulation occurs in vivo not tested
  8. 2021 High

    Tissue-specific knockouts revealed OTULIN's roles in endothelial cells (removing linear Ub from ALK1 to promote BMP9/Smad1/5 signaling and angiogenesis) and keratinocytes (preventing TNFR1/RIPK1-dependent necroptosis), while antiviral studies showed OTULIN deubiquitinates IRF3 to limit RIG-I-induced apoptosis and is itself degraded via caspase-3 cleavage and subsequent ubiquitination during viral infection.

    Evidence EC-specific OTULIN KO with ALK1 ubiquitination/deubiquitination assays; keratinocyte-specific KO with RIPK3/MLKL/FADD epistasis; IRF3 overexpression/KD with D31A mutagenesis and MS-identified K64/K197 ubiquitination

    PMID:34157307 PMID:34545182 PMID:34625556 PMID:34625557

    Open questions at the time
    • Whether ALK1 linear ubiquitination occurs in human endothelial disease
    • Relative contribution of necroptosis vs. apoptosis in keratinocytes varies between studies
    • Whether OTULIN degradation during viral infection is a host defense or viral evasion strategy
  9. 2022 High

    OTULIN haploinsufficiency in patient fibroblasts causes linear Ub accumulation and caveolin-1-dependent susceptibility to staphylococcal α-toxin, revealing a non-NF-κB, non-leukocytic immune function; separately, stress-induced OTULIN dimerization via disulfide bonds enables intermolecular self-deubiquitination at K64/K66, causing LUBAC dissociation and NF-κB overactivation.

    Evidence Patient fibroblast biochemistry with α-toxin cytotoxicity assays; OTULIN dimerization assays with K64/K66 mutagenesis under oxidative/genotoxic stress

    PMID:35587511 PMID:35939695

    Open questions at the time
    • Mechanism linking linear Ub to caveolin-1 accumulation not defined
    • Whether dimerization-triggered LUBAC dissociation operates in all cell types or is context-specific
    • Structural basis of the OTULIN dimer not determined
  10. 2023 High

    New pathway connections were established: myeloid OTULIN deficiency licenses RIPK3-dependent cell death that activates the NLRP3 inflammasome for IL-1β secretion independently of gasdermin D; STAT3 was identified as a linear Ub substrate in glioblastoma stem cells where OTULIN sustains STAT3 signaling; and SPATA2 was shown to compete with OTULIN for HOIP binding, providing an additional layer of LUBAC regulation.

    Evidence Myeloid OTULIN KO with RIPK3/NLRP3/gasdermin D epistasis; bio-orthogonal linear Ub probe with MS in GSCs; Cyld/Spata2 double-KO mouse with OTULIN epistasis

    PMID:36640323 PMID:36660824 PMID:38000038

    Open questions at the time
    • Whether NLRP3 activation is direct or secondary to DAMP release from dying cells
    • Linear ubiquitination sites on STAT3 not mapped
    • Whether SPATA2–OTULIN competition is regulated dynamically during signaling
  11. 2024 Medium

    A dominant-negative OTULIN C129S patient mutation demonstrated that catalytic inactivity without loss of LUBAC binding traps linear Ub on LUBAC and blocks LUBAC recruitment to the TNF receptor signaling complex, directly linking DUB activity to signaling complex assembly; separately, OTULIN was shown to stabilize GPX4 by deubiquitination, conferring cisplatin resistance.

    Evidence Patient cell biochemistry with TNFR1-SC Co-IP and TNF death assays; GPX4 ubiquitination assays with cisplatin resistance readout

    PMID:38630025 PMID:39721999

    Open questions at the time
    • Whether GPX4 deubiquitination involves Met1-linked chains specifically is not confirmed
    • Whether C129S mutation acts as a dominant negative in heterozygous carriers in all tissues
  12. 2026 High

    OTULIN was established as a negative regulator of RIG-I-dependent type I IFN production by removing linear ubiquitin from TRAF6 at K104/K142/K371, which otherwise facilitates TRAF6 K63-ubiquitination and MAVS association to amplify antiviral signaling.

    Evidence CRISPR KO with lentiviral rescue, TRAF6 site-specific mutagenesis, TRAF6-MAVS Co-IP, IFN reporter, MS identification of ubiquitination sites

    PMID:41802043

    Open questions at the time
    • Whether OTULIN acts on TRAF6 directly or through LUBAC removal is not fully distinguished
    • In vivo antiviral phenotype in OTULIN conditional KO not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full-length structure of OTULIN in complex with LUBAC, the complete in vivo substrate repertoire of OTULIN's DUB activity, the structural basis of OTULIN dimerization, and whether non-catalytic functions (SNX27/SCRIB interactions) contribute to disease phenotypes in patients.
  • No full-length OTULIN–LUBAC complex structure exists
  • Systematic in vivo substrate identification not performed
  • Non-catalytic functions not tested in genetic disease models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3 GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 1 R-HSA-9612973 Autophagy 1
Partners
DUSP14HOIPRIPK1SCRIBSNX27SPATA2TRAF6TRIM32
Complex memberships
LUBAC

Evidence

Reading pass · 32 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 Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad; mutation of Ub Glu16 reduces kcat 240-fold. OTULIN binds LUBAC and its overexpression prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Crystal structure, in vitro DUB assay, active-site mutagenesis, Co-IP, overexpression/knockdown Cell High 23746843
2013 OTULIN specifically disassembles Met1-linked polyubiquitin and restricts Met1-Ub accumulation after NOD2 stimulation. RIPK2 was identified as the predominant NOD2-regulated Met1-Ub substrate by affinity purification of Met1-Ub followed by quantitative proteomics. OTULIN-depleted cells spontaneously accumulate Met1-Ub on LUBAC components. siRNA knockdown, affinity purification of Met1-Ub + quantitative MS proteomics, overexpression Molecular cell High 23806334
2014 OTULIN binds LUBAC via a conserved PUB-interacting motif (PIM) that interacts with the PUB domain of the LUBAC component HOIP. Crystal structures and NMR reveal the molecular basis for the high-affinity interaction. Phosphorylation of OTULIN at Tyr56 within the PIM prevents HOIP binding; unphosphorylated OTULIN is part of the endogenous LUBAC complex. OTULIN must be present on LUBAC to restrict Met1-polyUb signaling. Crystal structure, NMR, Co-IP, phosphomimetic mutagenesis, endogenous complex analysis Molecular cell High 24726323
2014 The HOIP PUB domain binds the PIM of OTULIN (critical contact residue Tyr56) and also binds the chaperone VCP/p97. Phosphorylation of OTULIN Tyr56 negatively regulates HOIP binding. HOIP binding to OTULIN is required for recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent NF-κB pathway activation. Structural studies, phosphomimetic mutagenesis, Co-IP, reporter assay Molecular cell High 24726327
2014 Both CYLD and OTULIN interact with LUBAC via the PUB domain of HOIP in unstimulated cells. CYLD and OTULIN synergistically suppress LUBAC-mediated linear polyubiquitination and NF-κB activation. The HOIP–OTULIN interaction is also involved in OTULIN suppression of canonical Wnt signaling activated by LUBAC. Co-IP, cell-free ubiquitination assay, HOIP-null cell complementation, reporter assay Genes to cells Medium 24461064
2016 OTULIN is essential in vivo for preventing TNF-associated systemic inflammation. OTULIN deficiency in myeloid cells causes accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation, while deficiency in B and T cells leads to LUBAC degradation and downregulation of M1-polyUb signaling. Anti-TNF treatment rescues mouse phenotypes, placing TNF downstream of OTULIN. Four independent mouse knockout models, anti-TNF rescue, cell-type-specific deletion, biochemical analysis of M1-Ub levels 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 due to TNFR1- and RIPK1 kinase-dependent cell death. Combined loss of caspase-8 and RIPK3 rescues embryonic lethality. OTULIN and LUBAC function in a linear pathway. Catalytic-inactive knock-in mice, genetic epistasis (caspase-8/RIPK3 double KO rescue), biochemical LUBAC auto-ubiquitination assay Nature High 29950720
2019 OTULIN interacts with SNX27 (sorting nexin 27) via a C-terminal PDZ-binding motif (PDZbm) binding the cargo-binding PDZ domain of SNX27. Crystal structure of OTU domain with PDZ domain reveals a second interface contributing to high-affinity interaction. Via this association, OTULIN antagonizes SNX27-dependent cargo loading, SNX27–VPS26A retromer interaction, and endosome-to-plasma membrane trafficking—a non-catalytic function of OTULIN. MS interactome, crystal structure, Co-IP, endosomal trafficking assay, mutagenesis Nature communications High 31541095
2019 During apoptosis, OTULIN is cleaved by caspase-3 at Asp-31 into a C-terminal fragment that restricts caspase activation and cell death. During necroptosis, OTULIN is hyper-phosphorylated at Tyr-56, modulating RIPK1 ubiquitin dynamics and promoting cell death. DUSP14 was identified as an OTULIN phosphatase that dephosphorylates Tyr-56 and limits necroptosis. Mutagenesis (D31A), caspase assays, necroptosis assays, phosphatase identification by biochemistry Cell reports Medium 31825842
2019 OTULIN deficiency in patient-derived fibroblasts reduces LUBAC levels and impairs TNF response. In monocytes, OTULIN deficiency increases TNF/NF-κB signaling. Both cell types are sensitized to TNF-induced death. An OTULIN-Gly281Arg mutation reduces activity and stability in vitro and in cells. Patient-derived cells, biochemical assays, TNF stimulation, in vitro stability/activity assays EMBO molecular medicine Medium 30804083
2020 LUBAC and OTULIN localize to the phagophore area to regulate autophagy. OTULIN knockdown promotes autophagy initiation but blocks autophagosome maturation; excessive linear-ubiquitinated ATG13 is recruited to the phagophore for prolonged expansion, inhibiting maturation. LUBAC knockdown inhibits autophagy initiation. siRNA knockdown, immunofluorescence (LC3 puncta), autophagy flux assays, bacterial infection Autophagy Medium 32543267
2020 TRIM32 conjugates non-proteolytic polyubiquitin onto OTULIN; this polyubiquitin blocks the HOIP–OTULIN interaction, thereby activating NF-κB signaling. TRIM32 E3 ligase activity is essential for this effect, and TRIM32-mediated NF-κB activation is dependent on OTULIN (genetic complementation). MS proteomics of OTULIN complex, Co-IP, mutagenesis of TRIM32 E3 domain, genetic complementation Journal of molecular cell biology Medium 31504727
2020 ABL1/c-Abl phosphorylates OTULIN at Tyr56 upon genotoxic stress, enhancing OTULIN association with β-catenin. OTULIN inhibits linear ubiquitination of β-catenin, attenuating its K48-linked ubiquitination and proteasomal degradation, thereby activating Wnt/β-catenin signaling upon DNA damage. Co-IP, ubiquitination assays, kinase inhibition, mutagenesis, xenograft models Nature communications Medium 32770022
2020 OTULIN deficiency in liver triggers steatohepatitis and hepatocellular carcinoma independently of TNFR1 signaling; the pathology is associated with aberrant mTOR activation and is significantly reduced by rapamycin, placing OTULIN upstream of mTOR in hepatocytes. Liver-specific OTULIN knockout mice, genetic TNFR1 deletion, rapamycin treatment, histological and biochemical analysis Cell death and differentiation Medium 32231246
2020 Ablation of OTULIN in liver parenchymal cells triggers FADD- and RIPK1 kinase-dependent hepatocyte apoptosis that initiates liver disease. Genetic ablation of FADD completely rescues and kinase-inactive RIPK1 knock-in significantly protects mice, establishing FADD/RIPK1 as the cell death pathway downstream of OTULIN in hepatocytes. Type I interferons also contribute to disease. Hepatocyte-specific OTULIN KO, FADD KO epistasis, RIPK1 kinase-dead knock-in epistasis Cell reports High 32075762
2021 OTULIN deubiquitinates ALK1, removing linear ubiquitin chains that LUBAC conjugates onto ALK1. LUBAC-mediated linear ubiquitination of ALK1 inhibits its kinase activity and Smad1/5 activation; OTULIN reverses this to promote angiogenesis. EC-specific OTULIN deletion causes arteriovenous malformations. EC-specific OTULIN KO mice, in vitro ubiquitination/deubiquitination assays, Smad1/5 phosphorylation assays, ALK1 constitutively active rescue Molecular cell High 34157307
2021 Epidermis-specific OTULIN deficiency causes inflammatory skin lesions driven by TNFR1 signaling in keratinocytes requiring RIPK1 kinase activity. Loss of RIPK3 or MLKL largely rescues skin inflammation, implicating necroptosis as the primary mechanism. Combined loss of RIPK3 and FADD fully prevents lesions, showing redundant apoptosis contribution. MyD88 deficiency suppresses skin lesion development. Keratinocyte-specific OTULIN KO, RIPK3 KO, MLKL KO, FADD KO, RIPK1 kinase-dead knock-in, MyD88 KO epistasis Nature communications High 34625556 34625557
2021 SNX27 inhibits LUBAC-mediated linear ubiquitin chain formation and TNFα-induced NF-κB activation. Upon TNFα stimulation, the OTULIN–SNX27 complex localizes to the membrane-associated TNF receptor complex where OTULIN deubiquitinates linear polyubiquitin formed by LUBAC. Chemical inhibition of SNX27–retromer translocation (cholera toxin) prevents OTULIN membrane localization. Co-IP, membrane fractionation/localization, cholera toxin inhibition, NF-κB reporter assay Cell & bioscience Medium 34315543
2021 OTULIN deubiquitinates IRF3 (removing linear polyubiquitin), thereby inhibiting the RIG-I-induced apoptosis pathway (RIPA). In virus-infected cells, RIPA actively degrades OTULIN: caspase-3 cleaves OTULIN at Asp-31, generating a fragment ubiquitinated at K64 and K197 (identified by MS) and subsequently degraded by proteasomes. HOIP ubiquitinates OTULIN to trigger its degradation. Overexpression/KD, mutagenesis (D31A, K64/K197), MS identification of ubiquitinated residues, in vitro cleavage assay Cell death and differentiation Medium 34545182
2021 OTULIN deubiquitinates proteasome subunits; OTULIN deficiency causes proteasome dysregulation, which activates type I interferon signaling in patient cells and CRISPR-KO cell lines. CRISPR KO, patient PBMC analysis, proteasome activity assays, IFN signaling readouts Science advances Medium 34797715
2022 OTULIN haploinsufficiency causes accumulation of linear ubiquitin in dermal fibroblasts and leads to OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts (but not leukocytes), which facilitates cytotoxic damage by staphylococcal α-toxin, revealing a cell-intrinsic non-NF-κB mechanism for OTULIN in non-leukocytic immunity. Patient fibroblast analysis, Co-IP/biochemical caveolin-1 measurement, α-toxin cytotoxicity assay, linear Ub accumulation by WB Science High 35587511
2022 OTULIN undergoes linear ubiquitination at Lys64/66 in a LUBAC-dependent manner under unstressed conditions, which is required for OTULIN-LUBAC interaction. Upon genotoxic or inflammatory stress, OTULIN self-deubiquitinates this modification intermolecularly via dimerization, causing dissociation from LUBAC and NF-κB overactivation. Oxidative stress induces OTULIN dimerization via cysteine-mediated disulfide bonds. Mutagenesis, Co-IP, ubiquitination assays, dimerization assays, cell viability readout Proceedings of the National Academy of Sciences Medium 35939695
2023 OTULIN deficiency in myeloid/macrophages licenses RIPK3-mediated cell death, leading to NLRP3 inflammasome activation and IL-1β secretion independently of gasdermin D-mediated pyroptosis. Elevated serum IL-1β in myeloid-specific OTULIN-deficient mice is abolished by deleting either Ripk3 or Nlrp3, establishing the pathway: OTULIN deficiency → RIPK3-dependent death → NLRP3 → IL-1β. Myeloid-specific OTULIN KO, RIPK3 KO epistasis, NLRP3 KO epistasis, IL-1β ELISA, gasdermin D KO Science immunology High 38000038
2023 STAT3 is a direct substrate of linear ubiquitination; OTULIN removes linear ubiquitin from STAT3 in glioblastoma stem cells. Linear ubiquitination of STAT3 negatively regulates its activity by recruiting the phosphatase TC-PTP to STAT3. Overexpression of OTULIN in GSCs restricts STAT3 linear ubiquitination, drives persistent STAT3 signaling, and maintains stemness. Bio-orthogonal linear ubiquitin probe (NAEK-Ub) in live cells, MS substrate identification, Co-IP of TC-PTP with STAT3, OTULIN KD/OE Nucleic acids research Medium 36660824
2023 SPATA2 competes with OTULIN for binding to HOIP via a PIM and zinc finger domain, thereby promoting LUBAC auto-ubiquitination and counteracting OTULIN-mediated LUBAC deubiquitination. Increased pro-inflammatory signaling in Cyld−/−Spata2−/− cells depends on OTULIN, establishing SPATA2 as an independent OTULIN antagonist at LUBAC. Double-KO mouse models (Cyld/Spata2), epistasis with OTULIN, Co-IP, M1-Ub level analysis Cell reports Medium 36640323
2023 OTULIN interacts with SCRIB via its C-terminal PDZ-binding motif in HEK293 cells. Met1-linked ubiquitin chains associate with VANGL2 and PRICKLE1 (PCP complex components). OTULIN localizes to VANGL2-enriched cell-cell contacts in MDCK cells; OTULIN loss causes deficits in Wnt5a-induced filopodia extension and trafficking of VANGL2. Interactomic (BioID/AP-MS), Co-IP, live-cell imaging, siRNA knockdown Disease models & mechanisms Medium 37589075
2024 OTULIN prevents proteasomal degradation of GPX4 by reducing its ubiquitin level, conferring cisplatin resistance in osteosarcoma. OTULIN deubiquitinates GPX4, stabilizing it and blocking the mitochondrial apoptotic pathway. OTULIN KD/OE, GPX4 ubiquitination assay, co-IP, cisplatin resistance assay Journal of experimental & clinical cancer research Medium 39721999
2024 The dominant-negative OTULIN C129S mutation ablates deubiquitinase activity without affecting protein stability or binding to LUBAC and linear ubiquitin chains. Loss of catalytic activity leads to LUBAC auto-ubiquitination accumulation, inhibiting LUBAC recruitment to the TNF receptor signaling complex and promoting TNF-induced cell death. Patient cell biochemistry, mutagenesis, Co-IP of LUBAC with TNFR1-SC, TNF death assays The Journal of experimental medicine Medium 38630025
2024 OTULIN regulates ubiquitination of NCOA4, leading to NCOA4 depletion and FTH1 accumulation, protecting hepatocytes from APAP-induced ferroptosis by modulating the NCOA4-FTH1 complex involved in ferritin autophagy. OTULIN KD/OE, NCOA4 ubiquitination assay, Co-IP, in vivo APAP model International immunopharmacology Low 40158433
2024 LUBAC promotes and OTULIN restricts activation of AMPK. LUBAC and OTULIN interact with AMPK and control its M1-ubiquitination, regulating AMPK activation in response to glucose starvation and allosteric activation. LUBAC deficiency impairs autophagy induction and metabolic reprogramming during starvation. Co-IP, M1-ubiquitination assay of AMPK, LUBAC/OTULIN KO cells, mouse and human samples, Drosophila starvation assay bioRxivpreprint Medium bio_10.1101_2024.11.08.622598
2026 OTULIN deubiquitinates TRAF6 by removing linear ubiquitin chains at K104, K142, and K371, which are conjugated by LUBAC upon RNA virus infection. Linear ubiquitination of TRAF6 facilitates its K63-linked ubiquitination and strengthens its association with MAVS, amplifying antiviral RIG-I signaling. OTULIN acts as a negative regulator of RIG-I-dependent IFN-I production. OTULIN KO (CRISPR), lentiviral re-expression rescue, mutagenesis of TRAF6 K104/K142/K371, Co-IP of TRAF6-MAVS, IFN reporter assay, MS identification of ubiquitination sites Proceedings of the National Academy of Sciences High 41802043
2025 OTULIN promotes canonical Wnt signaling in keratinocytes by removing linear ubiquitin from β-catenin. In OTULIN-deficient keratinocytes, linearly ubiquitinated β-catenin accumulates and undergoes K48-linked ubiquitination and proteasomal degradation. Reduced Wnt signaling leads to TCF3 degradation, an essential survival factor, thus linking OTULIN's linear DUB activity to epithelial cell viability. Keratinocyte-specific KO, β-catenin linear ubiquitination assay, TCF3 measurement, β-catenin stabilization rescue bioRxivpreprint Medium bio_10.1101_2025.01.08.631848

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 401 23746843
2016 The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell 270 27523608
2017 CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell death and differentiation 218 28362430
2013 OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Molecular cell 216 23806334
2018 OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature 178 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 104 24461064
2019 OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO molecular medicine 95 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 73 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 56 29544517
2022 Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Science (New York, N.Y.) 49 35587511
2020 OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis. Cell reports 48 32075762
2021 OTULIN in NF-κB signaling, cell death, and disease. Trends in immunology 46 34074601
2021 OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice. Nature communications 44 34625557
2019 Regulation of the endosomal SNX27-retromer by OTULIN. Nature communications 42 31541095
2019 Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death. Cell reports 40 31825842
2021 OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. Nature communications 32 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 30 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 27 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 25 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.) 21 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 17 34545182
2024 Dominant negative OTULIN-related autoinflammatory syndrome. The Journal of experimental medicine 16 38630025
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
2024 A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome. The Journal of experimental medicine 13 38652464
2023 A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma. Nucleic acids research 13 36660824
2016 OTULIN deficiency causes auto-inflammatory syndrome. Cell research 13 27686184
2023 Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion. Science immunology 12 38000038
2021 SNX27-driven membrane localisation of OTULIN antagonises linear ubiquitination and NF-κB signalling activation. Cell & bioscience 12 34315543
2023 OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition. Journal of clinical immunology 9 38129331
2024 OTULIN-related conditions: Report of a new case and review of the literature using GenIA. Clinical immunology (Orlando, Fla.) 8 38914362
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 8 39721999
2023 OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection. Cell death & disease 8 37598207
2020 OTULIN couples WNT signaling to resistance in triple-negative breast cancer. Molecular & cellular oncology 7 33241111
2024 The Effect of Thymoquinone on the TNF-α/OTULIN/NF-κB Axis Against Cisplatin-İnduced Testicular Tissue Damage. Reproductive sciences (Thousand Oaks, Calif.) 6 38658488
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
2024 OTULIN's influence on neuroinflammation and pain modulation in trigeminal neuralgia. CNS neuroscience & therapeutics 5 39169794
2023 SPATA2 restricts OTULIN-dependent LUBAC activity independently of CYLD. Cell reports 5 36640323
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 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
2024 OTULIN Can Improve Spinal Cord Injury by the NF-κB and Wnt/β-Catenin Signaling Pathways. Molecular neurobiology 3 38561559
2024 Downregulation of otulin induces inflammasome activation in neutrophilic asthma. The Journal of allergy and clinical immunology 3 38599290
2024 OTULIN deficiency: focus on innate immune system impairment. Frontiers in immunology 3 38774872
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
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