Abstract
The M gene segment of influenza A virus has been shown to be a contributing factor to the high growth phenotype. However, it remains largely unknown why matrix protein 1 (M1), the major structural protein encoded by M gene, exhibits pH-dependent conformational changes during virus replication. Understanding the mechanisms underlying efficient virus replication can help to develop strategies not only to combat influenza infections but also to improve vaccine supplies. M(NLS-88R) and M(NLS-88E) are two M1 mutants differing by only a single amino acid: G88R vs G88E. G88R but not G88E was the compensatory mutation naturally selected by the virus after its nuclear localization signal was disrupted. Our study shows that, compared with M(NLS-88E) M1, M(NLS-88R) M1 dissociated quickly from viral ribonucleoproteins (vRNPs) at higher pH and took less time to dissemble in vitro, despite forming thicker matrix layer and having stronger association with vRNP in assembled virions. Correspondingly, M(NLS-88R) replicated more efficiently and was genetically more stable than M(NLS-88E). Crystallographic analysis indicated that M(NLS-88R) M1, like wild-type M1, is able to switch from a face-to-back-oriented conformation to a face-to-face-oriented conformation when pH drops from neutral to acidic, whereas G88E mutation causes M(NLS-88E) M1 to be trapped in a face-to-face-arranged conformation regardless of environmental pH. Our results suggest that maintaining M1 pH-dependent conformational flexibility is critical for efficient virus replication, and position 88 is a key residue controlling M1 pH-dependent conformational changes. Our findings provide insights into developing M1-based antiviral agents.Emerging Microbes & Infections (2017) 6, e108; doi:10.1038/emi.2017.96; published online 6 December 2017
Highlights
The viral core of influenza A virus (IAV) contains eight gene segments that are individually incorporated along with nucleoprotein (NP) into viral ribonucleoproteins.[1]
Using M(NLS-88R) and M(NLS-88E) as model viruses, we revealed that the transition from a face-to-back orientation at neutral pH to a face-toface orientation at acidic pH allows matrix protein 1 (M1) to quickly dissociate from viral ribonucleoproteins (vRNPs) for efficient replication
Our previous study indicated that M(NLS-88R) possessed much thicker M1 layer and had stronger M1–vRNP association in viral particles than M(NLS-88E) virions.[30]
Summary
The viral core of influenza A virus (IAV) contains eight gene segments that are individually incorporated along with nucleoprotein (NP) into viral ribonucleoproteins (vRNPs).[1] As the most abundant viral protein encoded by the M gene segment, matrix protein 1 (M1) forms a shell underneath a host cell-derived lipid biolayer to connect the vRNPs with the viral envelope in mature virions.[1,2] It has been reported that reassortment with the M gene segment of a high growth IAV, for example, A/PR/8/34 or A/WSN/33 (WSN), often generates a new virus with high growth potential,[3,4,5,6] suggesting M gene plays an important role in virus replication. Arrangement.[10,13,14] Acidic conditions (pH ~ 5.0 or lower) have been used to selectively isolate M1 from assembled virions.[15,16] These results indicate that M1 exhibits various conformations depending upon environmental pH. As the major structural protein in mature virions, the mechanism(s) by which M1 exhibits pH-dependent conformational changes during virus replication remains largely undefined
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