Alternative titles; symbols
HGNC Approved Gene Symbol: MARCHF3
Cytogenetic location: 5q23.2 Genomic coordinates (GRCh38): 5:126,867,714-127,030,558 (from NCBI)
MARCH3 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. MARCH3 appears to function in the endosomal recycling pathway (Fukuda et al., 2006).
Poxviruses and gamma-2 herpesviruses express ubiquitin ligases called K3 proteins that inhibit the surface expression of glycoproteins, including major histocompatibility complex 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 MARCH3. The deduced MARCH3 protein contains a short N terminus, followed by a RING-CH domain and 2 transmembrane domains. MARCH3 shares about 60% identity with MARCH2 (613332) in the RING-CH and transmembrane domains. Immunofluorescence analysis showed that epitope-tagged MARCH3 colocalized with a marker for endocytic or lysosomal vesicles.
Using RT-PCR, De Gassart et al. (2008) detected variable MARCH3 expression in all human cells and cell lines examined, including immature and mature dendritic cells, HeLa and B-cell lines, and monocytes.
Using Northern blot analysis, Fukuda et al. (2006) detected variable March3 expression in all rat tissues examined. Immunofluorescence microscopy detected endogenous MARCH3 in HeLa cells, where it partly colocalized with transferrin receptor (TFRC; 190010), an early endosome marker.
Fukuda et al. (2006) showed that the RING-CH finger domain of rat March3 functioned as an E3 ubiquitin ligase in an in vitro ubiquitination reaction. Overexpression of March3 in HeLa cells caused mislocalization of TGN46 (TGOLN2; 603062), an endosome protein that normally cycles between the plasma membrane and the trans-Golgi network (TGN), from the TGN to peripheral vesicles. Overexpression of March3 also interfered with uptake of transferrin (TF; 190000) through the endosomal recycling pathway. Immunoprecipitation analysis showed that epitope-tagged March3 interacted with March2 and with syntaxin-6 (STX6; 603944). Deletion of the C-terminal class I PDZ-binding motif caused accumulation of March3 in the endoplasmic reticulum (ER), suggesting that the PDZ-binding sequence is necessary for proper exit from the ER. Mutation analysis also showed that 2 critical cysteines within the RING-CH domain of March3 were necessary for targeting of March3 to peripheral vesicles.
Hartz (2010) mapped the MARCH3 gene to chromosome 5q23.2 based on an alignment of the MARCH3 sequence (GenBank AF055007) with the genomic sequence (GRCh37).
Patients with autosomal dominant adult-onset leukodystrophy (ADLD; 169500) have been found to have a duplication on chromosome 5 that includes all of the LMNB1 gene (150340) and part of the MARCH3 gene (see 150340.0001).
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]
Fukuda, H., Nakamura, N., Hirose, S. MARCH-III is a novel component of endosomes with properties similar to those of MARCH-II. J. Biochem. 139: 137-145, 2006. [PubMed: 16428329] [Full Text: https://doi.org/10.1093/jb/mvj012]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/29/2010.