title: MARCH8 inhibits HIV-1 infection by reducing virion incorporation of envelope glycoproteins.
abstract: Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING (really interesting new gene)-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins, including major histocompatibility complex (MHC)-II, CD86, interleukin (IL)-1 receptor accessory protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and the transferrin receptor. However, its physiological roles remain largely unknown. Here we identify MARCH8 as a novel antiviral factor. The ectopic expression of MARCH8 in virus-producing cells does not affect levels of lentivirus production, but it does markedly reduce viral infectivity. MARCH8 blocks the incorporation of HIV-1 envelope glycoprotein into virus particles by downregulating it from the cell surface, probably through their interaction, resulting in a substantial reduction in the efficiency of viral entry. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein is even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Notably, the endogenous expression of MARCH8 is high in monocyte-derived macrophages and dendritic cells, and MARCH8 knockdown or knockout in macrophages significantly increases the infectivity of virions produced by these cells. Our findings thus indicate that MARCH8 is highly expressed in terminally differentiated myeloid cells, and that it is a potent antiviral protein that targets viral envelope glycoproteins and reduces their incorporation into virions.
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tada
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.|Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tobiume
authors.affiliation: Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Yasuko
authors.identifier: http://orcid.org/0000-0002-1168-8846
authors.initials: Y
authors.lastname: Tsunetsugu-Yokota
authors.affiliation: Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.affiliation: Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Tokunaga
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D020868:Gene Silencing; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014771:Virion / Q000378:metabolism*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014759:Viral Envelope Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C568898:MARCHF8 protein, human; D044767:Ubiquitin-Protein Ligases