Ubiquitin carboxyl-terminal hydrolase 14 (USP14)
The protein contains 494 amino acids for an estimated molecular weight of 56069 Da.
Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins. Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Plays a role in the innate immune defense against viruses by stabilizing the viral DNA sensor CGAS and thus inhibiting its autophagic degradation. (updated: Jan. 31, 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.
- 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, is annotated as membranous in UniProt.
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Biological Process
Chemical synaptic transmission
Innate immune response
Negative regulation of endopeptidase activity
Negative regulation of ER-associated ubiquitin-dependent protein catabolic process
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein deubiquitination
Regulation of chemotaxis
Regulation of proteasomal protein catabolic process
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 607274
Ubiquitin-specific protease 14; usp14
Trna-guanine transglycosylase, 60-kd subunit
Tgt, 60-kd subunit
CLONING
Eukaryotes synthesize queuosine by the irreversible exchange of queuine for guanine at tRNA position 34, a reaction catalyzed by tRNA-guanine transglycosylase (TGT). Mammalian TGT appears to be a dimer of 60- and 43-kD subunits. Deshpande et al. (1996) determined that the purified rabbit 60-kD Tgt subunit, or Usp14, shares significant sequence identity with human TRE2 (USP6; 604334) and ORF8 (USP8; 603158), particularly in the conserved cys and his domains. Using the rabbit sequence, they identified an EST containing human USP14 and cloned the cDNA from a placenta cDNA library. The deduced human protein contains 494 amino acids and shares 98% sequence identity with the rabbit protein.MAPPING
The International Radiation Hybrid Mapping Consortium mapped the USP14 gene to chromosome 18 (TMAP SJGC-11272). Wilson et al. (2002) stated that 2 human neurologic disorders possibly involving alterations of synaptic function map to 18p near USP14: major affective disorder-1 (MAFD1; 125480) and schizophrenia disorder 8 (SCZD8; 603206).GENE FUNCTION
Lee et al. (2010) showed that USP14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in vivo and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress.ANIMAL MODEL
Mice that are homozygous with respect to the spontaneous mutation ax(J) in the ataxia (ax) gene develop severe tremors by 2 to 3 weeks of age followed by hindlimb paralysis and death by 6 to 10 weeks of age. Wilson et al. (2002) showed that ax encodes Usp14, one of the large family of cysteine proteases that specifically feed ubiquitin conjugates. Although Usp14 can cleave a ubiquitin-tagged protein in vitro, it is unable to process polyubiquitin, which is believed to be associated with the protein aggregates seen in Parkinson disease, spinocerebellar ataxia type 1 (SCA1; 164400), and gracile axonal dystrophy (GAD) in mice. The physiologic substrate of Usp14 may therefore contain a monoubiquitin side chain, the removal of which would regulate processes such as protein localization and protein activity. Expression of Usp14 is altered in homozygous ax(J) mice as a result of the insertion of an intracisternal A particle (IAP) into intron 5 of Usp14. In contrast to other neurodegenerative disorders such as Parkinson disease and SCA1 in humans and GAD in mice, neither ubiquitin-positive protein aggregates nor neuronal cell loss was detectable in the CNS of ax(J) mice. Instead, these mice had defects in synaptic transmission in both the central and peripheral nervous systems. These results suggested that ubiquitin proteases are important in regulating synaptic activity in mammals. ... More on the omim web site
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 607274 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed