Human MARCH1, 2, and 8 Block Ebola Virus Envelope Glycoprotein Cleavage via Targeting Furin P Domain

Abstract

Membrane-Associated Ring-CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes of action. Previous work proved that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates that human MARCH1 and MARCH2 share a similar pattern to MARCH8 in restricting EBOV GP-mediated viral replication. Human MARCH1 and MARCH2 retain EBOV GP in the trans-Golgi network (TGN), reduce its surface display, and impair EBOV GP-pseudotyped virions infectivity. Furthermore, we uncover that the host proprotein convertase (PC) furin could interact with human MARCH1/2 and EBOV GP intracellularly. Importantly, the furin P domain is confirmed to be recognized by MARCH1/2/8, which is critical for their blocking activities. Besides, bovine MARCH2 and murine MARCH1 also impair EBOV GP proteolytic processing. Altogether, our findings confirm that MARCH1/2 proteins of different species showed a relatively conserved feature in blocking EBOV GP proteolytic processing, which could provide a reference for subsequent antiviral studies and may facilitate the development of novel strategies to antagonize enveloped virus infection.