Alternative titles; symbols
HGNC Approved Gene Symbol: MARCHF4
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:216,257,865-216,372,483 (from NCBI)
MARCH4 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. MARCH4 reduces surface accumulation of several membrane glycoproteins by directing them to the endosomal compartment (Bartee et al., 2004).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) cloned KIAA1399. The deduced protein contains 452 amino acids. RT-PCR ELISA detected high expression in whole adult brain and moderate expression in fetal brain, fetal liver, spinal cord, and all individual adult brain regions examined.
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 MARCH4. The deduced MARCH4 protein contains a short N terminus, followed by a RING-CH domain and 2 transmembrane domains. MARCH4 shares 90% identity with MARCH9 (613336) in the RING-CH and transmembrane domains. Real-time PCR high expression in brain and placenta, weak expression in lung and pancreas, and little to no expression in other tissues examined. Immunofluorescence analysis showed that epitope-tagged MARCH4 colocalized with markers of the Golgi apparatus.
Gong et al. (2003) described a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes, and pathways. They found that P271, a novel protein with a single proline-rich domain that is closely related to human KIAA1399, is expressed predominantly in layer 2 and 5 pyramidal cells. The morphology of expressing cells was clearly evident, including the ramifications of basal dendrites within layer 5 and extension of the apical dendrite and its elaboration within layer 1 of the developing and adult cortex.
Bartee et al. (2004) showed that the isolated RING-CH domain of MARCH4 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), but not other E2 enzymes examined. Following transfection into HeLa cells, MARCH4 downregulated the surface expression of cotransfected CD4 (186940) and endogenous MHC I. Mutation analysis revealed that the RING-CH domain of MARCH4 was required for downregulation of MHC I surface expression, and additional sequences in the MARCH4 N- and C-terminal ends contributed to internalization. MHC I was internalized to lysosomes via multivesicular bodies, and inhibition of endosome acidification or expression of a dominant-negative VPS4 (see 609982) mutant abrogated MARCH4-induced MHC I internalization. Deletion of lysines in the tails of HLA-A2.1 (600642) and CD4 made these proteins resistant to MARCH9-induced degradation, suggesting that ubiquitination of these lysines is required for their uptake and degradation.
The International Radiation Hybrid Mapping Consortium mapped the KIAA1399 gene to chromosome 2 (SGC32061).
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. Virol. 78: 1109-1120, 2004. [PubMed: 14722266] [Full Text: https://doi.org/10.1128/jvi.78.3.1109-1120.2004]
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., Heintz, N. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425: 917-925, 2003. [PubMed: 14586460] [Full Text: https://doi.org/10.1038/nature02033]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]