HCFC1
Domain
The HCF repeat is a highly specific proteolytic cleavage signal.
The kelch repeats fold into a 6-bladed kelch beta-propeller called the beta-propeller domain which mediates interaction with HCFC1R1.
Function
Transcriptional coregulator (By similarity). Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion (By similarity). May negatively modulate transcriptional activity of FOXO3 (By similarity).
(Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.
Involvement in disease
Methylmalonic aciduria and homocystinuria, cblX type
MAHCX
An X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy, failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Proteolytically cleaved at one or several PPCE--THET sites within the HCF repeats (PubMed:10920196, PubMed:21285374, PubMed:7590226). Further cleavage of the primary N- and C-terminal chains results in a 'trimming' and accumulation of the smaller chains. Cleavage is promoted by O-glycosylation (PubMed:21285374, PubMed:28302723, PubMed:28584052).
O-glycosylated. GlcNAcylation by OGT promotes proteolytic processing.
Ubiquitinated. Lys-1807 and Lys-1808 are ubiquitinated both via 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. BAP1 mediated deubiquitination of 'Lys-48'-linked polyubiquitin chains; deubiquitination by BAP1 does not seem to stabilize the protein.
Tissue Specificity
Highly expressed in fetal tissues and the adult kidney. Present in all tissues tested.
Cellular localization
- Cytoplasm
- Nucleus
- HCFC1R1 modulates its subcellular localization and overexpression of HCFC1R1 leads to accumulation of HCFC1 in the cytoplasm (PubMed:12235138). Non-processed HCFC1 associates with chromatin. Colocalizes with CREB3 and CANX in the ER.
Alternative names
HCF1, HFC1, HCFC1, Host cell factor 1, HCF, HCF-1, C1 factor, CFF, VCAF, VP16 accessory protein