9.A.73.  The Virus Matrix Protein (VMP) Family 

Lipid-enveloped viruses contain a lipid bilayer coat that protects their genome and helps to facilitate entry into the host cell. Filoviruses are lipid-enveloped viruses that have up to 90% clinical fatality and include Marbug (MARV) and Ebola (EBOV). These pleomorphic filamentous viruses enter the host cell through their membrane-embedded glycoprotein and then replicate using just seven genes encoded in their negative-sense RNA genome. EBOV budding occurs from the inner leaflet of the plasma membrane (PM) and is driven by the matrix protein VP40, which is the most abundantly expressed protein of the virus. VP40 expressed in mammalian cells alone can trigger budding of filamentous virus-like particles (VLPs) that are nearly indistinguishable from authentic EBOV. VP40, such as matrix proteins from other viruses, has been shown to bind anionic lipid membranes. VP40 selectively interacts with the inner leaflet of the PM and assembles into a filamentous lipid enveloped particle (Stahelin 2014).  A loop region in the NZ-terminal domain of the protein is important for viral association with the membrane, virus assembly, budding and egress (Adu-Gyamfi et al. 2014), and VP40 induces vesiculation of phosphatidyl serine (PS)-enriched membranes (Soni and Stahelin 2014). In fact, phosphatidyl serine is essential for association of dimers to generate active hexamers followed by assembly and budding (Adu-Gyamfi et al. 2015). The VP40 structure is available (Oda et al. 2016). Phosphoinositides (PIs) are important for efficient VP40 localization to the plasma membrane. PI(4,5)P2 is essential for VP40 assembly at the plasma membrane (PM) and subsequent virus like particle formation.  It is required for formation of extensive oligomers of VP40. This suggests that PS and PI(4,5)P2 play different roles in VP40 assembly, where PS regulates formation of hexamers from VP40 dimers and PI(4,5)P2 stabilizes and/or induces extensive VP40 oligomerization (Johnson et al. 2016).  VP40 induces clustering of PS and PI in the PM (Gc et al. 2016). A cationic C-terminal domain of VP40 and structural rearrangements control its interactions with phosphatidyl serine (Del Vecchio et al. 2018). It has been shown that VP40 can induce phospholipid flipping in vitro (RV Stahelin, personal communication). Several other virus matrix proteins of the Mononegavirales have been suggested to be homologous.

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