Ubiquilin-4 (UBQLN4)
The protein contains 601 amino acids for an estimated molecular weight of 63853 Da.
Regulator of protein degradation that mediates the proteasomal targeting of misfolded, mislocalized or accumulated proteins (PubMed:15280365, PubMed:27113755, PubMed:29666234, PubMed:30612738). Acts by binding polyubiquitin chains of target proteins via its UBA domain and by interacting with subunits of the proteasome via its ubiquitin-like domain (PubMed:15280365, PubMed:27113755, PubMed:30612738). Key regulator of DNA repair that represses homologous recombination repair: in response to DNA damage, recruited to sites of DNA damage following phosphorylation by ATM and acts by binding and removing ubiquitinated MRE11 from damaged chromatin, leading to MRE11 degradation by the proteasome (PubMed:30612738). MRE11 degradation prevents homologous recombination repair, redirecting double-strand break repair toward non-homologous end joining (NHEJ) (PubMed:30612738). Specifically recognizes and binds mislocalized transmembrane-containing proteins and targets them to proteasomal degradation (PubMed:27113755). Collaborates with DESI1/POST in the export of ubiquitinated proteins from the nucleus to the cytoplasm (PubMed:29666234). Also plays a role in the regulation of the proteasomal degradation of non-ubiquitinated GJA1 (By similarity). Acts as an adapter protein that recruits UBQLN1 to the autophagy machinery (PubMed:23459205). Mediates the association of UBQLN1 with autophagosomes and the autophagy-related protein LC3 (MAP1LC3A/B/C) and may assist in the maturation of autophagoso (updated: May 8, 2019)
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.
- 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:rs2297792 | |
| ALS |
Biological Process
Autophagy
Cellular response to DNA damage stimulus
DNA repair
Negative regulation of autophagosome maturation
Negative regulation of double-strand break repair via homologous recombination
Regulation of proteasomal ubiquitin-dependent protein catabolic process
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 605440
Ubiquilin 4; ubqln4
Ataxin-1 ubiquitin-like interacting protein; a1u
C1orf6
Connexin 43-interacting protein, 75-kd; cip75
CLONING
By a yeast 2-hybrid screen of an adult human brain cDNA library, Davidson et al. (2000) isolated cDNA clones which they used to assemble a complete cDNA encoding the 601-amino acid ataxin-1 ubiquitin-like interacting protein (A1U). Sequence comparison revealed that A1U contains an N-terminal ubiquitin-like region, placing it within a large family of similar proteins. In addition, A1U shows substantial homology to human UBQLN2 (300264), a protein that binds the ATPase domain of the HSP70-like STCH protein (601100). Expression analyses demonstrated that A1U mRNA is widely expressed as a 4.0-kb transcript and is present in Purkinje cells, the primary site of spinocerebellar ataxia-1 (SCA1; 164400) cerebellar pathology. The A1U protein localized to the nucleus and cytoplasm of transfected COS-1 cells. Sequences important for the transport of A1U into the nucleus appeared to lie within the C terminus. In the nucleus, A1U colocalized with mutant ataxin-1 (ATX1; 601556), further demonstrating that A1U interacts with ataxin-1. Using Northern and Western blot analyses, Su et al. (2010) detected variable Cip75 mRNA and protein expression in all mouse tissues examined.GENE FUNCTION
Davidson et al. (2000) suggested that A1U may link ataxin-1 with the chaperone and ubiquitin/proteasome pathways and that ataxin-1 may function in the formation and regulation of multimeric protein complexes within the nucleus. Monoubiquitination usually marks proteins for endocytosis, whereas lys48-linked tetraubiquitination typically marks proteins for proteasomal degradation. Su et al. (2010) showed that mouse Cip75 interacted with both synthetic monoubiquitinated and tetraubiquitinated proteins in vitro and with a host of endogenous ubiquitinated proteins in HeLa cell lysates. Cip75 also interacted with nonubiquitinated Cx43 (GJA1; 121014) in the endoplasmic reticulum. Even in the absence of Cx43 ubiquitination, Cip75 stimulated Cx43 proteasomal degradation.MAPPING
Davidson et al. (2000) found that AIU (UBQLN4) is the same as C1orf6, which was mapped by FISH to chromosome 1q21 by Fogli et al. (1999). ... More on the omim web site
May 11, 2019: 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 605440 was added.