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Last update 08 May 2025

OTULIN

Last update 08 May 2025

Basic Info

Synonyms

Deubiquitinating enzyme otulin, FAM105B, family with sequence similarity 105, member B

+ [7]

Introduction

Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:24726323, PubMed:24726327, PubMed:26997266, PubMed:27523608, PubMed:27559085, PubMed:28919039, PubMed:35170849, PubMed:35587511). Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex (PubMed:23708998). Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex (PubMed:23746843, PubMed:23806334). OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex (PubMed:26670046). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent pro-inflammatory signaling (PubMed:23806334).

Drugs associated with OTULIN

US20250051313

Patent Mining

Target

OTULIN

Mechanism-

Active Org.

Sitryx Therapeutics Ltd.

Originator Org.

Sitryx Therapeutics Ltd.

Active Indication

Cardiovascular Diseases [+13]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with OTULIN

100 Translational Medicine associated with OTULIN

0 Patents (Medical) associated with OTULIN

117

Literatures (Medical) associated with OTULIN

04 May 2025·Autophagy

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival

Article

Author: Winklhofer, Konstanze F. ; Mari, Muriel C. ; Balta, Denise ; Scheuer, Christoph ; Behrends, Christian ; Zellner, Suzanne ; Vandrey, Julia ; Zein, Laura ; Zunke, Friederike ; Van Wijk, Sjoerd J. L. ; Dietrich, Marvin ; Bader, Verian ; Weinelt, Nadine

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A₁; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.

01 May 2025·International Immunopharmacology

OTULIN orchestrates NCOA4-FTH1 complex to alleviate APAP-induced hepatocyte Ferroptosis

Article

Author: Yang, Xiang ; Meng, Ying ; Jiang, Zhitao ; Gao, Liyuan ; Chang, Xiaoyan ; Han, Yi ; Li, Jian

BACKGROUNDAcetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI) and can progress to acute liver failure (ALF). Hepatocyte death is widely recognized as the central event in APAP-induced liver injury; however, the underlying mechanisms are complex and not yet fully elucidated. Ferroptosis, a recently identified form of programmed cell death characterized by glutathione (GSH) depletion and disruption of cellular redox homeostasis, shares key features with APAP-induced hepatotoxicity. This study aimed to investigate the role of ferroptosis in APAP-induced liver injury and to explore potential therapeutic targets.EXPERIMENTAL APPROACHESC57BL/6 mice were administered APAP to evaluate ferroptosis and hepatic injury in vivo through histological and biochemical analyses. A range of molecular techniques, along with the establishment of stable cell lines, were employed to elucidate the underlying mechanisms in vitro.RESULTSWe demonstrated that APAP disrupts iron homeostasis and promotes hepatocyte ferroptosis. OTULIN, a deubiquitinase involved in linear ubiquitination, was found to regulate the ubiquitination modification of NCOA4, leading to NCOA4 depletion and FTH1 accumulation. This process enhanced the resistance and adaptability of hepatocytes to APAP-induced damage.CONCLUSIONOur findings reveal that OTULIN modulates the NCOA4-FTH1 complex to protect against APAP-induced hepatocyte ferroptosis. Targeted upregulation of OTULIN in hepatocytes may represent a promising therapeutic strategy for APAP-induced DILI.

01 Mar 2025·ACR Open Rheumatology

Failure to Close: An Unexpected Surgical Complication Reveals OTULIN Haploinsufficiency

Article

Author: Kim, Charlotte F. ; Vogel, Tiphanie P. ; Nguyen, Jessica ; Ramirez, Andrea A.

ObjectiveThe aim of this report is to raise awareness of a rare inborn error of immunity (IEI) that can predispose to inflammatory disease and infection risk by describing a patient case.MethodsWe reviewed clinical findings, laboratory and pathology evaluations, and genetic results.ResultsA 13‐year‐old female patient with a history of prematurity and spastic diplegic cerebral palsy underwent planned orthopedic procedures to correct chronic gait abnormalities. Her postoperative course was complicated by fevers associated with respiratory failure and wound dehiscence at the surgical sites. A chest computed tomography scan revealed bilateral consolidative pneumonia with parapneumonic effusions. Infectious and clinical immune evaluations were unremarkable. She had resolution of fevers and respiratory failure with broad‐spectrum antibiotics; however, her wounds became progressively ulcerative and necrotic. A skin biopsy demonstrated skin ulceration with acute neutrophilic inflammation. She was started on glucocorticoids and infliximab infusions with prompt improvement in wound healing. Subsequently, a clinical genetic panel revealed a heterozygous variant in OTULIN c.787C>T, p.Arg263Trp, located at the same amino acid previously reported in OTULIN haploinsufficiency. OTULIN haploinsufficiency is a rare IEI that predisposes to life‐threatening necrosis of the skin and lungs, often in response to Staphylococcus aureus infection.ConclusionOTULIN haploinsufficiency predisposes to increased susceptibility to infections and tissue‐specific necrosis often triggered by infection. Recognition of this rare IEI is important because patients with OTULIN haploinsufficiency may require combined antibiotic and immunomodulatory therapy.

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