M-phase phosphoprotein 8 (MPHOSPH8)
The protein contains 860 amino acids for an estimated molecular weight of 97182 Da.
Heterochromatin component that specifically recognizes and binds methylated 'Lys-9' of histone H3 (H3K9me) and promotes recruitment of proteins that mediate epigenetic repression (PubMed:20871592, PubMed:26022416). Mediates recruitment of the HUSH complex to H3K9me3 sites: the HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2 (PubMed:26022416, PubMed:28581500). Binds H3K9me and promotes DNA methylation by recruiting DNMT3A to target CpG sites; these can be situated within the coding region of the gene (PubMed:20871592). Mediates down-regulation of CDH1 expression (PubMed:20871592). Also represses L1 retrotransposons in collaboration with MORC2 and, probably, SETDB1, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). The HUSH complex is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed (PubMed:30487602). (updated: May 8, 2019)
Protein identification was indicated in the following studies:
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
Negative regulation of gene expression, epigenetic
Negative regulation of single stranded viral RNA replication via double stranded DNA intermediate
Negative regulation of transcription, DNA-templated
Positive regulation of DNA methylation-dependent heterochromatin assembly
Regulation of DNA methylation
The reference OMIM entry for this protein is 611626
M-phase phosphoprotein 8; mphosph8
Mpp8
Two-hybrid-associated protein with ranbpm 3; twa3
CLONING
Using N-terminally truncated RANBPM (RANBP9; 603854) as bait in a yeast 2-hybrid screen of a human lymphocyte cDNA library, Umeda et al. (2003) obtained a partial cDNA encoding the C-terminal half of MPHOSPH8, which they called TWA3.GENE FUNCTION
Tchasovnikarova et al. (2015) used a nonlethal forward genetic screen in near-haploid KBM7 cells to search for genes required for epigenetic repression in human cells. The authors identified the HUSH (human silencing hub) complex, comprising 3 proteins, TASOR (FAM208A; 616493), MPP8, and periphilin (608150). This complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased trimethylation of histone-3 on lys9 (H3K9me3) both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Tchasovnikarova et al. (2015) concluded that their results suggested that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 (604396) is required for further H3K9me3 deposition to maintain transcriptional silencing.MAPPING
The International Radiation Hybrid Mapping Consortium mapped the MPHOSPH8 gene to chromosome 13 (TMAP RH66674). ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 611626 was added.
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).