Molecular Mechanism And The Effect On Viral Replication Of Human Parainfluenza Virus Type 3 Induced Autophagy

HPIV3 is one of the primary pathogens that cause severe respiratory tract diseases including bronchiolitis, pneumonia, and croup in infants and young children. However, no valid antiviral therapy or vaccine is currently available. Thus, a more complete understanding of the factors that influence HPIV3 replication and pathogenesis is therefore necessary to aid in the development of vaccines and antiviral therapies. In this study, we sought to determine how the autophagy process is particularly targeted by HPIV3 and to identify the molecular partners underlying the execution and regulation of the autophagy process between the virus and hostAutophagy is a multistep process in which cytoplasmic components, including invading pathogens, are captured by autophagosomes that subsequently fuse with degradative lysosomes. Negative strand RNA viruses, including Paramyxoviruses, have been shown to alter autophagy but the molecular mechanisms remain largely unknown. We demonstrate that Human parainfluenza virus type 3 (HPIV3) induces incomplete autophagy by blocking autophagosome-lysosome fusion, resulting in increased virus production. The viral phosphoprotein (P) is necessary and sufficient to inhibit autophagosome degradation. P binds to SNAP29 and inhibits its interaction with syntaxinl7, thereby preventing these two host SNARE proteins from mediating autophagosome-lysome fusion. Incomplete autophagy and resultant autophagosome accumulation increase extracellular viral production but do not affect viral protein synthesis. These findings highlight a how viruses can block autophagosome degradation by disrupting the function of SNARE proteins.Mitophagy is a form of autophagy selectively remove the mitochondria while many antiviral immune adaptor proteins are localized in mitochondria. HPIV3 infection induces autophagy, but whether and how HPIV3 infection induces mitophagy and the mechanism remains largely poor known. Here we show that M of HPIV3 interacts directly with a mitochondrial Tu translation elongation factor (TUFM) to translocate to mitochondria; ubiqintinated M associates with LC3 and functions as autophagy adaptor to induce mitophagy and TUFM is critical in this induction.Thus our results shown that ubiqintinated M interacts with LC3 and TUFM to serve as autophagy receptor, an unanticipated finding firstly to show viral matrix protein is sufficient to induce mitophagy through bridging autophagosomes and mitochondria.