Arenavirus Stable Signal Peptide Is the Keystone Subunit for Glycoprotein Complex Organization

Bederka, Lydia H.; Bonhomme, Cyrille J.; Ling, Emily L.; Buchmeier, Michael J.

The arenavirus glycoprotein complex is expressed as a polyprotein precursor that undergoes two cleavage events. First, the stable signal peptide (SSP) is cleaved by cellular signal peptidase within the endoplasmic reticulum (ER). This 58-amino-acid protein is retained as a stable subunit and is critical for downstream, mature glycoprotein complex formation (10) (11) (12) . Second, SSP traffics with immature GP1/2 precursor (amino acids 59 to 498), which undergoes cleavage by the SKI-1/S1P enzyme within the Golgi stacks to yield the GP1 and GP2 subunits (13, 14) . The three independent subunits, consisting of the SSP, GP1, and GP2, traffic to the plasma membrane for viral assembly and egress (15) (16) (17) (18) . These three subunits interact noncovalently at the virion surface to bind with host cell receptors to initiate infectivity. The GP1 subunit interacts with the known cellular receptors: ␣-dystroglycan (␣-DG) for the OW arenaviruses and transferrin receptor 1 (TfR1) for the NW viruses (19, 20) . Recent studies using next-generation technologies provided evidence for the involvement of additional host factors for both Junín virus and Lassa virus entry (21, 22) . The acidification of endocytic vesicles induces irreversible dissociation of the GP1 subunit from the remaining GP2 and SSP subunits, followed by a conformational change within the GP2 subunit to reveal the fusion domains which, in concert with SSP, induce fusion events between the virion and the host membrane to deliver the viral core to the newly infected cell cytoplasm (23, 24) .