MARCH8 inhibits viral infection by two different mechanisms

• Published in: eLife Vol. 9
• Main Authors: Zhang, Yanzhao, Tada, Takuya, Ozono, Seiya, Kishigami, Satoshi, Fujita, Hideaki, Tokunaga, Kenzo
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 11.08.2020; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Amino acids; Antibodies; Antiviral drugs; antiviral factor; envelope; Experiments; Glycoproteins; Health aspects; HEK293 Cells; HIV; HIV Infections - virology; HIV-1; HIV-1 - physiology; Human immunodeficiency virus; Humans; Hypotheses; Infection; Infectivity; Lysine; MARCH8; Microbiology and Infectious Disease; Molecular modelling; Mutants; Mutation; Plasmids; Protein transport; Proteins; Rhabdoviridae Infections - virology; Short Report; Stomatitis; Tyrosine; tyrosine motif; Ubiquitin; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology; Ubiquitination; Vesiculovirus - physiology; Viral Envelope Proteins - genetics; Viral infections; Virions; Viruses; HIV-1; antiviral factor; envelope; infectious disease; ubiquitination; microbiology; tyrosine motif; MARCH8; human; virus
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.57763

Membrane-associated RING-CH 8 (MARCH8) inhibits infection with both HIV-1 and vesicular stomatitis virus G-glycoprotein (VSV-G)-pseudotyped viruses by reducing virion incorporation of envelope glycoproteins. The molecular mechanisms by which MARCH8 targets envelope glycoproteins remain unknown. Here, we show two different mechanisms by which MARCH8 inhibits viral infection. Viruses pseudotyped with the VSV-G mutant, in which cytoplasmic lysine residues were mutated, were insensitive to the inhibitory effect of MARCH8, whereas those with a similar lysine mutant of HIV-1 Env remained sensitive to it. Indeed, the wild-type VSV-G, but not its lysine mutant, was ubiquitinated by MARCH8. Furthermore, the MARCH8 mutant, which had a disrupted cytoplasmic tyrosine motif that is critical for intracellular protein sorting, did not inhibit HIV-1 Env-mediated infection, while it still impaired infection by VSV-G-pseudotyped viruses. Overall, we conclude that MARCH8 reduces viral infectivity by downregulating envelope glycoproteins through two different mechanisms mediated by a ubiquitination-dependent or tyrosine motif-dependent pathway.