OTUD1

Last update 08 May 2025

Basic Info

Synonyms

DUBA-7, DUBA7, OTDC1

+ [3]

Introduction

Deubiquitinating enzyme that specifically hydrolyzes 'Lys-63'-linked polyubiquitin to monoubiquitin (PubMed:23827681). Required for the stability and translation of a subset mRNAs with a high abundance of rare codons by mediating deubiquitination of 40S ribosomal protein RPS10/eS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:36445135). The abundance of rare codons in mRNAs can limit the translation rate and can lead to ribosome collisions that trigger activation of ribosome quality control (RQC) pathway by ZNF598 (PubMed:36445135). OTUD1-mediated deubiquitination prevents activation of the RQC and subsequent dissociation of ribosomes and stimulates formation of polysomes and translation (PubMed:36445135).

100 Clinical Results associated with OTUD1

100 Translational Medicine associated with OTUD1

0 Patents (Medical) associated with OTUD1

Literatures (Medical) associated with OTUD1

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 Apr 2025·Bioorganic & Medicinal Chemistry

Identification and optimization of a small molecule inhibitor of the ovarian tumor protease of the Crimean-Congo hemorrhagic fever virus

Article

Author: Liessmann, Fabian ; Schoeder, Clara T ; Urban, Nicole ; Rieger, Dominic ; Tretbar, Maik ; Schaefer, Michael ; Icker, Maik ; Meiler, Jens ; Schlegel, Phillip ; Beckmann, Lorenz

Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne disease with fatality rates of up to 30 %. Currently, there are no vaccines or specific antivirals available. The genome of the CCHF virus (CCHFV) encodes an ovarian tumor (OTU) protease with a deubiquitinating activity that is responsible for the evasion of the innate immune response. Therefore, the inhibition of the OTU protease could provide a strategy for the treatment of CCHFV infections. In this study, we screened for small-molecule inhibitors of CCHFV OTU using a fluorescent ubiquitin rhodamine 110 assay. We identified and validated a 2-aminothiazole hit compound (IC₅₀ = 42.3 μM) followed by structure-activity relationships (SAR) studies resulting in a new inhibitor of the CCHFV OTU protease. The most active derivative is a competitive CCHFV OTU inhibitor with an IC₅₀ value of 10.7 μM. Selectivity studies revealed that the ubiquitin-specific peptidase 7 (USP7), ubiquitin C-terminal hydrolase 5 (UCHL5), OTU deubiquitinase 1 (OTUD1), and Cezanne are also inhibited by this newly developed inhibitor indicating binding to conserved regions of the ubiquitin-binding site within the deubiquitinase superfamilies. Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure-activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.

01 Mar 2025·Cell Proliferation

Ubiquitin‐Proteasome System in Periodontitis: Mechanisms and Clinical Implications

Review

Author: Ma, Yilin ; Ma, Lulu ; Liang, Guang ; He, Yunuo ; Ma, Jun ; Pan, Xingbei ; Huang, Shengbin ; Chen, Shuhong ; Wu, Tong ; Wu, Shengzhuang ; Wang, Huining ; Zhao, Zheyu ; Yin, Lei ; Sun, Xiaoyu ; Jia, Ruiwei

ABSTRACTThe progression of periodontitis, a bacteria‐driven inflammatory and bone‐destructive disease, involves myriad cellular and molecular mechanisms. Protein regulation significantly influences the pathogenesis and management of periodontitis. However, research regarding its regulatory role in periodontitis remains relatively limited. The ubiquitin‐proteasome system (UPS), which mainly involves ubiquitination by E3 ubiquitin ligases (E3s) and deubiquitination by deubiquitinating enzymes (DUBs), is the primary intracellular and non‐lysosomal mechanism of protein degradation. Recent studies have provided compelling evidence to support the involvement of UPS in periodontitis progression. Increasing evidence indicated that E3s, such as CUL3, Nedd4‐2, Synoviolin, FBXL19, PDLIM2, TRIMs and TRAFs, modulate inflammatory responses and bone resorption in periodontitis through multiple classical signalling pathways, including NLRP3, GSDMD, NF‐κB, Wnt/β‐catenin and Nrf2. Meanwhile, DUBs, including OTUD1, A20, CYLD, UCH‐L1 and USPs, also broadly modulate periodontitis progression by regulating signalling pathways such as NF‐κB, Wnt/β‐catenin, NLRP3, and BMP2. Therefore, the modulation of E3s and DUBs has proven to be an effective therapy against periodontitis. This review provides a comprehensive overview of the regulatory role of ubiquitinating and deubiquitinating enzymes in periodontitis progression and the underlying mechanisms. Finally, we summarise several chemical and genetic methods that regulate UPS enzymes and pave the way for the development of targeted therapies for periodontitis.

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OTUD1

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