Ubiquitin thioesterase otulin (OTULIN)
The protein contains 352 amino acids for an estimated molecular weight of 40263 Da.
Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:26997266, PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327, PubMed:28919039). 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 proinflammatory signaling (PubMed:23806334). (updated: Nov. 7, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs11953822 | |
| dbSNP:rs9312870 | |
| dbSNP:rs9312870 | |
| AIPDS | |
| AIPDS |
Biological Process
Canonical Wnt signaling pathway
Innate immune response
Negative regulation of inflammatory response
Negative regulation of NF-kappaB transcription factor activity
Nucleotide-binding oligomerization domain containing 2 signaling pathway
Protein linear deubiquitination
Protein ubiquitination
Regulation of canonical Wnt signaling pathway
Regulation of tumor necrosis factor-mediated signaling pathway
Sprouting angiogenesis
Wnt signaling pathway
The reference OMIM entry for this protein is 615712
Otu deubiquitinase with linear linkage specificity; otulin
Family with sequence similarity 105, member b; fam105b
Gumby, mouse, homolog of; gum
DESCRIPTION
Ubiquitination of proteins is an important posttranslational modification that regulates diverse cellular processes. There are 8 different types of polyubiquitin (polyUb) linkages, the most common of which are lys48 and lys63 linked to the C-terminal glycine (gly76) of Ub. PolyUb can also be linked in a linear chain by the linear ubiquitin assembly complex (LUBAC), which catalyzes the linkage of gly76 of 1 Ub monomer to the N-terminal methionine (met1) of the next Ub monomer. OTULIN is a deubiquitinating enzyme that regulates LUBAC activity and reverses formation of linear met1-linked polyUb chains (Keusekotten et al., 2013).CLONING
Rivkin et al. (2013) stated that mouse Otulin, which they called Gumby, is a deubiquitinating enzyme characterized by an ovarian tumor (OTU) domain fold with a cys-his-asn catalytic triad. Immunofluorescence analysis detected Gumby in developing mouse vasculature and branchial arches and in neural crest cells, with enrichment in a subset of endothelial cells. Using a bioinformatic screen to identify OTU domain-containing enzymes, Keusekotten et al. (2013) identified OTULIN, which they cloned from a human brain cDNA library. The deduced 352-amino acid protein has a short N-terminal helical domain, followed by a large OTU domain (amino acids 88 through 352). Database analysis suggested ubiquitous OTULIN expression in human tissues. Fluorescence-tagged OTULIN was expressed in the cytoplasm of transfected HEK293 cells. Orthologs of OTULIN were found in vertebrates and some invertebrates, but not in D. melanogaster or C. elegans.MAPPING
Gross (2014) mapped the OTULIN gene to chromosome 5p15.2 based on an alignment of the OTULIN sequence (GenBank GENBANK BC007706) with the genomic sequence (GRCh37). Rivkin et al. (2013) reported that the mouse Otulin gene maps to chromosome 15.GENE FUNCTION
By expressing mouse Gumby in HEK293 cells, Rivkin et al. (2013) found that Gumby interacted with Hoip (RNF31; 612487), a key LUBAC component. Gumby inhibited accumulation of linear polyUb chains and subsequent activation of NF-kappa-B (see 164011)-dependent transcription. Inhibition of LUBAC by Gumby required its catalytic activity. Yeast 2-hybrid and immunoprecipitation analyses revealed that Gumby also interacted with DVL2 (602151), which is required for Wnt signaling. By assaying recombinant enzyme against all 8 diubiquitin (diUb) linkage types and ser76-to-met1 tetraUb substrates, Keusekotten et al. (2013) found that human OTULIN showed strict specificity in binding and hydrolyzing met1-diUb substrates. OTULIN also hydrolyzed longer met1-linked polyUb chains. When overexpressed in HEK293 cells, OTULIN removed met1-polyUb from NEMO (IKBKG; 300248) and dampened LUBAC-mediated NF-kappa-B signaling. Conversely, knockdown of OTULIN increased met1-polyUb, IKK (see 603258) activation, and NF-kappa-B signaling after TNF-alpha (TNF; 191160) stimulation. However, both overexpression and knockdown of OTULIN sensitized cells to TNF-alpha-induced apoptosis, suggesting a complex role for met1 linkages in TNF-alpha receptor (see 191190) signaling. Protein pull-down assays revealed that OTULIN interacted with LUBAC subunits, including HOIP, and targeted met1-polyUb HOIP, suggesting that LUBAC undergoes activating autoubiquitination that OTULIN can prevent. Keusekotten et al. (2013) predicted that OTULIN may target met1-linked Ub chains, regardless of where they are attached, rather ... More on the omim web site
Nov. 16, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: OMIM entry 615712 was added.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for OTULIN