The study investigates the antiviral activities of human MARCH1, MARCH2, and MARCH8 proteins against Ebola virus (EBOV) glycoprotein (GP) maturation. The researchers found that these proteins, including human MARCH1 and MARCH2, bovine MARCH2, and murine MARCH1, inhibit EBOV GP cleavage and reduce its cell surface expression. Specifically, they retain EBOV GP at the trans-Golgi network (TGN), preventing its transport to the cell surface and impairing viral infectivity. The interaction between host proprotein convertase furin and MARCH1/2/8 is crucial for their blocking activities, with the furin P domain being recognized by these proteins. The study also demonstrates that MARCH1/2/8 form a complex with furin and EBOV GP at the TGN, blocking furin-cleavage of GP. This conserved antiviral mechanism provides insights into the development of novel antiviral strategies.The study investigates the antiviral activities of human MARCH1, MARCH2, and MARCH8 proteins against Ebola virus (EBOV) glycoprotein (GP) maturation. The researchers found that these proteins, including human MARCH1 and MARCH2, bovine MARCH2, and murine MARCH1, inhibit EBOV GP cleavage and reduce its cell surface expression. Specifically, they retain EBOV GP at the trans-Golgi network (TGN), preventing its transport to the cell surface and impairing viral infectivity. The interaction between host proprotein convertase furin and MARCH1/2/8 is crucial for their blocking activities, with the furin P domain being recognized by these proteins. The study also demonstrates that MARCH1/2/8 form a complex with furin and EBOV GP at the TGN, blocking furin-cleavage of GP. This conserved antiviral mechanism provides insights into the development of novel antiviral strategies.