E3 ubiquitin-protein ligase HUWE1 (HUWE1)
The protein contains 4374 amino acids for an estimated molecular weight of 481891 Da.
E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15989957, PubMed:19713937, PubMed:15567145, PubMed:15767685, PubMed:18488021, PubMed:17567951, PubMed:19037095, PubMed:20534529). Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1 (PubMed:15989957). Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair (PubMed:19713937). Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4 (PubMed:15567145, PubMed:15767685, PubMed:15989956). Ubiquitinates MFN2 to negatively regulate mitochondrial fusion in response to decreased stearoylation of TFRC (PubMed:26214738). Binds to an upstream initiator-like sequence in the preprodynorphin gene. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN (PubMed:18488021). May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation (PubMed:17567951). Mediates polyubiquitination of isoform 2 of PA2G4 (PubMed:19037095). Acts in concert with MYCBP2 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquination and degradation of NR1D1 (PubMed:20534529). (updated: Aug. 12, 2020)
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.
(right-click above to access to more options from the contextual menu)
Biological Process
Base-excision repair
Cell differentiation
Circadian regulation of gene expression
Golgi organization
Histone ubiquitination
Membrane fusion
Negative regulation of mitochondrial fusion
Neutrophil degranulation
Positive regulation of mitophagy in response to mitochondrial depolarization
Positive regulation of protein catabolic process
Positive regulation of protein targeting to mitochondrion
Positive regulation of protein ubiquitination
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein monoubiquitination
Protein polyubiquitination
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 300697
Hect, uba, and wwe domains-containing protein 1; huwe1
Upstream regulatory element-binding protein 1; ureb1
Ure-binding protein 1
Lasu1
Kiaa0312
DESCRIPTION
The HUWE1 gene encodes an E3 ubiquitin ligase (summary by Froyen et al., 2012).CLONING
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned HUWE1, which they designated KIAA0312. RT-PCR analysis detected low HUWE1 expression in all tissues examined. By database analysis, Liu et al. (2005) identified full-length human HUWE1, which they called LASU1. The deduced 4,374-amino acids protein has a calculated molecular mass of 481.9 kD. It has 2 N-terminal domains similar to domains found in an S. cerevisiae HECT domain ligase, Tom1, followed by a ubiquitin (191339)-associated (UBA) domain, a ubiquitin-interacting motif (UIM), a WWE domain, and a C-terminal HECT domain. The deduced full-length mouse Lasu1 protein contains 4,377 amino acids. Froyen et al. (2012) found expression of the Huwe1 gene in several mouse tissues, including cortex, hippocampus, tongue, eye, kidney, liver, adrenal gland, and fibroblasts.GENE FUNCTION
Gu et al. (1994) found that a recombinant 310-amino acid Ureb1 protein from rat brain specifically bound to the upstream regulatory element (URE) in the promoter region of the rat preprodynorphin (PDYN; 131340) gene. Tyrosine phosphorylation of Ureb1 increased transcription of a reporter gene containing the URE. Liu et al. (2005) showed that Lasu1 from bovine testis was a Ubc4 (UBE2D2; 602962)-dependent E3 ligase that ubiquitinated histones H1 (see 142709), H2A (see 613499), H2B (see 609904), H3 (see 602810), and H4 (see 602822) in vitro. Ubc4 isoform-1 and a testis-specific Ubc4 isoform were the preferred E2s. Mass spectrometry and size analysis suggested that Lasu1 functions as a monomer.MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the HUWE1 gene to chromosome X. Liu et al. (2005) mapped the mouse Huwe1 gene to chromosome X.CYTOGENETICS
Using X chromosome-specific array comparative genomic hybridization (array CGH), Froyen et al. (2008) identified overlapping microduplications of chromosome Xp11.22 in affected individuals from 6 unrelated families with nonsyndromic X-linked mental retardation (MRX17; 300705). Subsequent PCR analysis showed that the duplicated regions varied from 0.4 to 0.8 Mb with a common minimal overlapping region that contained 2 candidate genes, HSD17B10 (300256) and HUWE1, both of which showed 2- to 5-fold overexpression in blood cells from affected individuals. Froyen et al. (2012) reported 6 additional families with nonsyndromic X-linked mental retardation associated with duplications at Xp11.22 (300705). All patients had mild to moderate intellectual disability, but some were able to attend school. Most patients had some additional variable features, but these features were not consistent enough to form a discernible pattern. All female carriers were phenotypically normal. Microarray analysis identified 6 different but overlapping duplications of chromosome Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated with the phenotype. Combined with the cytogenetic data from the 6 families reported by Froyen et al. (2008), Froyen et al. (2012) found that the common minimal region of overlap is 228 kb, which contains the HUWE1 gene and excludes the HSD17B10 gene. Cell lines from patients showed 2-fold increased expression of HUWE1, and studies in 4 female carriers showed skewed X inactivation. The authors concluded that HUWE1 is the dosage-sensitive gene for wh ... More on the omim web site
Aug. 24, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 11, 2019: 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
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300697 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed