Abstract
Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the MARCH family of RING finger E3 ubiquitin ligases and down-regulates several membrane proteins (e.g. major histocompatibility complex II [MHC-II], CD86, and transferrin receptor). We recently reported that MARCH8 also targets HIV-1 envelope glycoproteins and acts as an antiviral factor. However, it remains unclear whether other family members might have antiviral functions similar to those of MARCH8. Here we show that MARCH1 and MARCH2 are MARCH family members that reduce virion incorporation of envelope glycoproteins. Infectivity assays revealed that MARCH1 and MARCH2 dose-dependently suppress viral infection. Treatment with type I interferon enhanced endogenous expression levels of MARCH1 and MARCH2 in monocyte-derived macrophages. Expression of these proteins in virus-producing cells decreased the efficiency of viral entry and down-regulated HIV-1 envelope glycoproteins from the cell surface, resulting in reduced incorporation of envelope glycoproteins into virions, as observed in MARCH8 expression. With the demonstration that MARCH1 and MARCH2 are antiviral MARCH family members as presented here, these two proteins join a growing list of host factors that inhibit HIV-1 infection.
Highlights
Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the membrane-associated RING-CH (MARCH) family of RING finger E3 ubiquitin ligases and down-regulates several membrane proteins
We recently reported that MARCH8 targets HIV-1 envelope glycoproteins and acts as an antiviral factor
Treatment with type I interferon enhanced endogenous expression levels of MARCH1 and MARCH2 in monocyte-derived macrophages. Expression of these proteins in virus-producing cells decreased the efficiency of viral entry and down-regulated HIV-1 envelope glycoproteins from the cell surface, resulting in reduced incorporation of envelope glycoproteins into virions, as observed in MARCH8 expression
Summary
To examine whether other MARCH family members that are expressed in HIV-1 target cells would inhibit HIV-1 infection, we newly created plasmids expressing family members of MARCH (MARCH1, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6, MARCH7, and MARCH9) by PCRamplifying their complementary DNAs. We showed that the antiviral activity of the MARCH1 and MARCH2 proteins was similar to that observed previously for MARCH8 [25] Both MARCH1 and MARCH2 can down-regulate HIV-1 Env glycoproteins from the cell surface, thereby inhibiting virion incorporation of Env and leading to decreased entry efficiency, which results in the reduction of viral infectivity, exactly as MARCH8. Because our preliminary data suggest that MARCH8 can interact with both HIV-1 Env and VSV-G through TM interactions, we assume that especially MARCH1, whose TM domain is highly homologous to that of MARCH8, may bind to these envelope glycoproteins, leading to cell surface down-regulation of these viral proteins This needs to be elucidated with further experiments. Further investigations that probe whether the inhibitory activity of these MARCH family members against viral envelope glycoproteins could be linked to their ability to down-regulate cellular transmembrane proteins will help us to understand the molecular basis of the host defense mechanisms of these proteins
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