Alternative titles; symbols
HGNC Approved Gene Symbol: MARCHF1
Cytogenetic location: 4q32.2-q32.3 Genomic coordinates (GRCh38): 4:163,524,298-164,384,019 (from NCBI)
MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH proteins add ubiquitin (see 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH1 downregulates the surface expression of major histocompatibility complex (MHC) class II molecules (see 142880) and other glycoproteins by directing them to the late endosomal/lysosomal compartment (Bartee et al., 2004; Thibodeau et al., 2008; De Gassart et al., 2008).
Poxviruses and gamma-2 herpesviruses express ubiquitin ligases called K3 proteins that inhibit the surface expression of glycoproteins, including 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 MARCH1. The deduced MARCH1 protein contains a short N terminus, followed by a RING-CH domain and 2 transmembrane domains. MARCH1 shares over 90% identity with MARCH8 (613335) in the RING-CH and transmembrane domains. Real-time PCR analysis detected highest MARCH1 expression in lymph node, followed by spleen and lung. Much lower expression was detected in most other tissues examined. Immunofluorescence analysis showed that epitope-tagged MARCH1 was expressed in a punctate pattern that partly overlapped with endocytic or lysosomal vesicles.
Using RT-PCR, De Gassart et al. (2008) detected MARCH1 expression predominantly in immature human dendritic cells and in a human B-cell line. Little or no expression was detected in mature dendritic cells, HeLa cells, and monocytes.
Bartee et al. (2004) showed that the isolated RING-CH domain of MARCH1 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 UBCH3 (CDC34; 116948) or UBCH5A (UBE2D1; 602961), but not UBCH2 (UBE2H; 601082). Following transfection into HeLa cells, MARCH1 downregulated the surface expression of cotransfected B7.2 (CD86; 601020) 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). Addition of IL10 (124092) increased MARCH1 mRNA expression over 40-fold, whereas other MARCH family members were affected only weakly or not at all. Knockdown of MARCH1 via small interfering RNA reversed IL10-induced MHC II downregulation. HLA-DR was mono- and polyubiquitinated in MARCH1-transfected HeLa cells. Peptide-loaded MHC II was also ubiquitinated. Immunoprecipitation analysis and fluorescence energy transfer microscopy showed that MARCH1 and HLA-DR colocalized in intracellular vesicles. Thibodeau et al. (2008) concluded that MARCH1 mediates the immunosuppressive effect of IL10 on antigen presentation in monocytes via ubiquitination and degradation of MHC II molecules.
De Gassart et al. (2008) found that overexpression of MARCH1 promoted ubiquitination of the HLA-DR beta chain (HLA-DRB; see 142857), but not the HLA-DR alpha chain, in human monocyte-derived dendritic cells. Mutation analysis showed that MARCH1 ubiquitinated HLA-DRB on lys225. Overexpression of MARCH1 reduced surface expression of mature HLA-DR complexes and enhanced accumulation of HLA-DR in late endosomal/lysosomal compartments. Downregulation of MARCH1 via small interfering RNA in immature dendritic cells resulted in increased surface levels of HLA-DR and CD86 and reduced levels of ubiquitinated HLA-DR. De Gassart et al. (2008) observed maturation-dependent downregulation of MARCH1 in lipopolysaccharide-activated dendritic cells, resulting in upregulation of MHC class II molecules at the cell surface. They concluded that MARCH1 is a major regulator of HLA-DR trafficking.
Hartz (2010) mapped the MARCH1 gene to chromosome 4q32.2-q32.3 based on an alignment of the MARCH1 sequence (GenBank AK00675) 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]
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]