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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2910

Nomenclature: otulin

Family: C101: OTULIN peptidase

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 352 5p15.2 OTULIN OTU deubiquitinase with linear linkage specificity 5
Mouse - 352 15 B1 Otulin OTU deubiquitinase with linear linkage specificity
Rat - 353 2 Otulin OTU deubiquitinase with linear linkage specificity
Previous and Unofficial Names Click here for help
gumby | Fam105b | family with sequence similarity 105, member B
Database Links Click here for help
Specialist databases
MEROPS C101.001 (Hs)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Enzyme Reaction Click here for help
EC Number:
Description Reaction Reference
Deubiquitinase that cleaves linear ubiquitin linkages Specifically cleaves ubiquitin linkages at Met1 5
Immunopharmacology Comments
Otulin is reported as a negative regulator of inflammation and autoimmunity [1].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Physiological Functions Click here for help
Hydrolyses Met1-linked ubiquitin chains to prevent undue proinflammatory signaling in response to immune receptor stimulation.
Species:  Human
Tissue:  Cell lines transfected with human otulin
References:  3,5
Negative regulator of inflammation and autoimmunity.
Species:  Human
References:  1,5
Physiological Functions Comments
Proteins with ubiquitination at Met1 (a.k.a. linear ubiquitination) are important regulators of nuclear factor-κB (NF-κB) transcription factors and immune response/immune system homeostasis. Otulin is the only deubiquitinase known to cleave linear ubiquitin linkages. Otulin interacts with the HOIP component of the linear ubiquitin chain assembly complex (LUBAC), a complex which is associated with many immune receptors and ubiquitinates a range of targets [2,5,8]. Met1-linked ubiquitination in immune signalling is discussed further in [4] and [3].
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  OTULIN-related autoinflammatory syndrome (ORAS)
Description: A potentially fatal inherited autoimmune disease. Premature newborns display severe idiopathic inflammatory symptoms, developing repeated episodes of systemic inflammation (diarrhea, elevated serum C-reactive protein) without evidence of infection. The affected babies develop painful swollen joints, elevated immunoglobulin levels and serum autoantibodies.
References:  1,7
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human Leu272Pro 815T>C 1
General Comments
Otulin is considered to be one member of a family of enzymes with predicted cysteine protease activity known as the OTU-like cysteine proteases. These enzymes, many of which appear to have deubiquitinase activity, all contain a domain homologous to the Ovarian Tumour (OTU) gene in Drosophila. Catalytic activity is thought to be conveyed by the conserved cysteine and histidine residues and may require the aspartate residue [6]. MEROPS classifies this enzyme in peptidase clan CA as its tertiary structure reveals a papain-like fold [8].


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1. Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, McHale D, Maher ER, McKenzie ANJ, Komander D. (2016) The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell, 166 (5): 1215-1230.e20. [PMID:27523608]

2. Elliott PR, Nielsen SV, Marco-Casanova P, Fiil BK, Keusekotten K, Mailand N, Freund SM, Gyrd-Hansen M, Komander D. (2014) Molecular basis and regulation of OTULIN-LUBAC interaction. Mol Cell, 54 (3): 335-48. [PMID:24726323]

3. Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, Gyrd-Hansen M. (2013) OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell, 50 (6): 818-30. [PMID:23806334]

4. Fiil BK, Gyrd-Hansen M. (2014) Met1-linked ubiquitination in immune signalling. FEBS J, 281 (19): 4337-50. [PMID:25060092]

5. Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D et al.. (2013) OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell, 153 (6): 1312-26. [PMID:23746843]

6. Makarova KS, Aravind L, Koonin EV. (2000) A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae. Trends Biochem Sci, 25 (2): 50-2. [PMID:10664582]

7. MRC scientists. Major breakthrough identifies cause and treatment of fatal autoimmune disease. Accessed on 17/08/2016. Modified on 17/08/2016. MRC Laboratory of Molecular Biology,

8. Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, Huang H, Dunham WH, Fukumura R, Xie G et al.. (2013) The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature, 498 (7454): 318-24. [PMID:23708998]

How to cite this page

C101: OTULIN peptidase: otulin. Last modified on 17/08/2016. Accessed on 30/05/2024. IUPHAR/BPS Guide to PHARMACOLOGY,