otulin

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2910

Nomenclature: otulin

Gene and Protein Information
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
gumby \| Fam105b \| family with sequence similarity 105, member B

Previous and Unofficial Names

gumby | Fam105b | family with sequence similarity 105, member B

Database Links
Specialist databases
MEROPS	C101.001 (Hs)
Other databases
Alphafold	Q96BN8 (Hs), Q3UCV8 (Mm)
BRENDA	3.4.19.12
Ensembl Gene	ENSG00000154124 (Hs), ENSMUSG00000046034 (Mm), ENSRNOG00000012017 (Rn)
Entrez Gene	90268 (Hs), 432940 (Mm), 100362554 (Rn)
Human Protein Atlas	ENSG00000154124 (Hs)
KEGG Enzyme	3.4.19.12
KEGG Gene	hsa:90268 (Hs), mmu:432940 (Mm), rno:100362554 (Rn)
Pharos	Q96BN8 (Hs)
RefSeq Nucleotide	NM_138348 (Hs), NM_001013792 (Mm), NP_001289818 (Rn), NM_001302889 (Rn)
RefSeq Protein	NP_612357 (Hs), NP_001013814 (Mm)
UniProtKB	Q96BN8 (Hs), Q3UCV8 (Mm)
Wikipedia	OTULIN (Hs)

Enzyme Reaction

EC Number: 3.4.19.12
	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].

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

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
Tissue:
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

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.

Role:

Faliure of otulin deubiquitinase activity results in spontaneous and uncontrolled immune system activation, leading to death if untreated.

Drugs:

The anti-TNFα antibody infliximab resolves ORAS symptoms, although it is not yet approved for this condition (August 2016). It is approved as a therapy for other autoimmune and inflammatory diseases, including rheumatoid arthritis and Crohn's disease.

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].

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].

References

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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, https://www2.mrc-lmb.cam.ac.uk/major-breakthrough-identifies-cause-treatment-fatal-autoimmune-disease/

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]