Ubiquitin carboxyl-terminal hydrolase 15 (USP15)
The protein contains 981 amino acids for an estimated molecular weight of 112419 Da.
Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:33093067). May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulat (updated: June 2, 2021)
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.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
BMP signaling pathway
Histone H2B conserved C-terminal lysine deubiquitination
Monoubiquitinated protein deubiquitination
Negative regulation of transforming growth factor beta receptor signaling pathway
Pathway-restricted SMAD protein phosphorylation
Positive regulation of RIG-I signaling pathway
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein deubiquitination
Regulation of proteasomal protein catabolic process
Transforming growth factor beta receptor signaling pathway
Ubiquitin-dependent protein catabolic process
Viral process
Molecular Function
Cysteine-type endopeptidase activity
Identical protein binding
Lys48-specific deubiquitinase activity
SMAD binding
Thiol-dependent deubiquitinase
Thiol-dependent ubiquitinyl hydrolase activity
Transforming growth factor beta receptor binding
Ubiquitin modification-dependent histone binding
The reference OMIM entry for this protein is 604731
Ubiquitin-specific protease 15; usp15
DESCRIPTION
Ubiquitin (191339), a highly conserved protein involved in the regulation of intracellular protein breakdown, cell cycle regulation, and stress response, is released from degraded proteins by disassembly of the polyubiquitin chains. The disassembly process is mediated by ubiquitin-specific proteases (USPs). Also see USP1 (603478).CLONING
By screening human brain cDNAs for those encoding proteins larger than 50 kD, Nagase et al. (1998) identified a partial cDNA encoding USP15, which they called KIAA0529. RT-PCR analysis detected USP15 expression in skeletal muscle, kidney, heart, placenta, liver, thymus, lung, and ovary, with little or no expression in other tissues. By searching an EST database for sequences related to USP4 (603486), Baker et al. (1999) identified a full-length cDNA encoding USP15. The 952-amino acid USP15 protein contains the conserved cysteine and histidine boxes present in all USPs.GENE FUNCTION
Baker et al. (1999) found that, like USP4, USP15 could cleave the ubiquitin-proline bond. TGFB (190180) and bone morphogenetic proteins (BMPs; see 112264) phosphorylate receptor-activated SMADs (e.g., SMAD1; 601595), which then associate with SMAD4 (600993) to regulate gene expression. Using a small interfering RNA screen to identify deubiquitylating enzymes (DUB) required for TGFB and BMP activity, Inui et al. (2011) identified human USP15 as a DUB for receptor-activated SMADs. USP15 was required for TGFB and BMP responses in both mammalian cells and frog embryos. Biochemical analysis showed that USP15 primarily opposed receptor-activated SMAD monoubiquitylation by targeting the DNA-binding domains of receptor-activated SMADs, thus preventing promoter recognition. Inui et al. (2011) concluded that USP15 is critical for the occupancy of endogenous target promoters by the SMAD complex and adds a layer of control by which the ubiquitin system regulates TGFB biology.MAPPING
Nagase et al. (1998) mapped the USP15 gene to chromosome 12 by radiation hybrid analysis. Using FISH, Baker et al. (1999) mapped the USP15 gene to 12q14. ... More on the omim web site
July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 604731 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed