Direct Visualization of Ebola Virus Fusion Triggering in the Endocytic Pathway

Spence, Jennifer S.; Krause, Tyler B.; Mittler, Eva; Jangra, Rohit K.; Chandran, Kartik

occurs primarily through a macropinocytosis-like process, and the virus traffics through the endocytic pathway (16) (17) (18) . Proteolytic cleavage of GP1 by a class of low-pH-activated proteases, cysteine cathepsins, removes the C-terminal glycan cap and mucin domain sequences (19) to reveal a receptor-binding domain. This newly exposed GP1 domain interacts with Niemann-Pick C1 (NPC1), which serves as an obligate intracellular receptor for filoviruses (20, 21) . While cathepsin cleavage and subsequent NPC1 binding are indispensable for infection, they are themselves insufficient to mediate release of the viral genome to the cytoplasm (22) . A final trigger for fusion of viral and endosomal membranes by GP2 has been postulated but not demonstrated (23, 24) , and which precise endosomal compartment actually supports fusion is unknown.