Date Published: November 21, 2013
Publisher: Public Library of Science
Author(s): Qian Liu, Jacquelyn A. Stone, Birgit Bradel-Tretheway, Jeffrey Dabundo, Javier A. Benavides Montano, Jennifer Santos-Montanez, Scott B. Biering, Anthony V. Nicola, Ronald M. Iorio, Xiaonan Lu, Hector C. Aguilar, Sean Whelan.
Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.
The Paramyxoviridae is a medically-important negative-sense single-stranded RNA enveloped virus family that includes measles (MeV), mumps (MuV), parainfluenza (PIV), respiratory syncytial (RSV), Newcastle disease (NDV), human metapneumo- (HMPV), and the henipa-viruses Nipah (NiV) and Hendra (HeV). NiV and HeV cause high mortality rates in humans, approaching 75% in recent NiV outbreaks ; death is associated with syncytium formation, vasculitis, pneumonia, and encephalitis. These biosafety level 4 (BSL4) pathogens possess a broad mammalian host range , animal-to-human, and human-to-human transmission , , and pose bio- and agro-terrorism threats to global health and economy. Thus, NiV is classified as a category C priority pathogen in the USA NIH/NIAID research agenda.
Our results reveal a comprehensive mechanism of cell receptor-induced NiV membrane fusion triggering. Upon ephrinB2 binding, the NiV-G head undergoes at least two conformational steps in the head that result in exposure of a NiV-G stalk domain that interacts with and triggers F (Fig. 7). To our knowledge, this is the most detailed mechanistic molecular picture of paramyxovirus attachment protein linking receptor binding to F-triggering to date. Additionally, the headless NiV-G prematurely triggers F in virions, causing the loss of viral entry (Fig. 3), implying a crucial role for the NiV-G head in preventing premature F-triggering by a G stalk domain until receptor binding occurs.