Alternative titles; symbols
HGNC Approved Gene Symbol: MARCHF8
Cytogenetic location: 10q11.21-q11.22 Genomic coordinates (GRCh38): 10:45,454,585-45,594,907 (from NCBI)
MARCH8 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH enzymes add ubiquitin (see 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH8 induces the internalization of several membrane glycoproteins (Goto et al., 2003; Bartee et al., 2004).
Kaposi sarcoma-associated herpesvirus (KSHV) modulator of immune recognition (MIR) proteins function as E3 ubiquitin ligases for immune recognition-related molecules. The MIR catalytic domain is a plant homeodomain (PHD) of the BKS (bovine herpesvirus-4, KSHV, and swinepox virus) subclass, or a BKS-PHD domain. By searching databases for proteins containing a BKS-PHD domain, followed by PCR and 5-prime RACE of a human BJAB B-cell cDNA library, Goto et al. (2003) cloned MARCH8, which they designated MIR. The deduced 291-amino acid protein has an N-terminal BKS-PHD domain, followed by 2 transmembrane domains. Both the N and C termini were predicted to be cytoplasmic. RT-PCR analysis detected MIR expression in neonatal brain and in adult lymph node, spleen, and placenta, but not in other tissues examined. It was also detected in monocytes and immature dendritic cells, but not in lymphocytes.
Poxviruses and gamma-2 herpesviruses express ubiquitin ligases called K3 proteins that inhibit the surface expression of glycoproteins, including major histocompatibility complex (MHC) class I molecules (see 142800). By searching a database for sequences similar to the functional domains of viral K3 proteins, Bartee et al. (2004) identified 9 human MARCH proteins, including MARCH8. The deduced MARCH8 protein contains a short N terminus, followed by a RING-CH domain and 2 transmembrane domains. MARCH8 shares over 90% identity with MARCH1 (613331) in the RING-CH and transmembrane domains. Real-time PCR analysis detected variable expression of MARCH8 in all human tissues examined, with highest expression in lung. Immunofluorescence analysis showed that epitope-tagged MARCH8 was expressed in a punctate pattern that partly overlapped with endocytic or lysosomal vesicles.
Using RT-PCR, De Gassart et al. (2008) detected high MARCH8 expression in immature and mature human dendritic cells and in HeLa and human B-cell lines, with lower expression in monocytes.
Goto et al. (2003) showed that overexpression of MIR in human cells downregulated surface expression of B7-2 (CD86; 601020), a costimulatory molecule for MHC II (see 142860)-mediated antigen presentation. Overexpression of MIR did not downregulate surface expression of MHC I molecules. The BKS-PHD domain of MIR showed ubiquitin ligase activity in an in vitro ubiquitination assay, and downregulation of surface B7-2 required ubiquitination of B7-2 on cytoplasmic lysines, which was followed by lysosomal degradation of B7-2. Mutation analysis revealed that the ubiquitin ligase activity of MIR and downregulation of surface B7-2 required conserved zinc-binding cysteines within the BKS-PHD domain of MIR. Immunoprecipitation analysis revealed that both wildtype MIR and a ligase-dead MIR mutant interacted directly with B7-2.
Bartee et al. (2004) showed that the isolated RING-CH domain of MARCH8 functioned as an E3 ubiquitin ligase in a reaction containing ubiquitin, ATP, an E1 ubiquitin-activating enzyme (see UBE1; 314370), and the E2 ubiquitin-conjugating enzyme UBCH2 (UBE2H; 601082) or UBCH5A (UBE2D1; 602961), but not UBCH3 (CDC34; 116948). Following transfection into HeLa cells, MARCH8 downregulated the surface expression of cotransfected B7.2 and endogenous TFR (TFRC; 190010) and FAS (TNFRSF6; 134637).
Thibodeau et al. (2008) showed that transfection of MARCH1 and MARCH8 into CD4 (186940)-positive human monocytes downregulated surface expression of all 3 MHC II isotypes, i.e., HLA-DR (see HLA-DRA; 142860), -DQ (see HLA-DQA1; 146880), and -DP (see HLA-DPA1; 142880).
Hartz (2010) mapped the MARCH8 gene to chromosome 10q11.21 based on an alignment of the MARCH8 sequence (GenBank BC025394) with the genomic sequence (GRCh37).
Bartee, E., Mansouri, M., Nerenberg, B. T. H., Gouveia, K., Fruh, K. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J. Virology 78: 1109-1120, 2004. [PubMed: 14722266] [Full Text: https://doi.org/10.1128/jvi.78.3.1109-1120.2004]
De Gassart, A., Camosseto, V., Thibodeau, J., Ceppi, M., Catalan, N., Pierre, P., Gatti, E. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Nat. Acad. Sci. 105: 3491-3496, 2008. [PubMed: 18305173] [Full Text: https://doi.org/10.1073/pnas.0708874105]
Goto, E., Ishido, S., Sato, Y., Ohgimoto, S., Ohgimoto, K., Nagano-Fujii, M., Hotta, H. c-MIR, a human E3 ubiquitin ligase, is a functional homolog of herpesvirus proteins MIR1 and MIR2 and has similar activity. J. Biol. Chem. 278: 14657-14668, 2003. [PubMed: 12582153] [Full Text: https://doi.org/10.1074/jbc.M211285200]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/29/2010.
Thibodeau, J., Bourgeois-Daigneault, M.-C., Huppe, G., Tremblay, J., Aumont, A., Houde, M., Bartee, E., Brunet, A., Gauvreau, M.-E., de Gassart, A., Gatti, E., Baril, M., Cloutier, M., Bontron, S., Fruh, K., Lamarre, D., Steimle, V. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Europ. J. Immun. 38: 1225-1230, 2008. [PubMed: 18389477] [Full Text: https://doi.org/10.1002/eji.200737902]