Glycoprotein (Gn) And Nucleocapsid Protein (Np) Of Hantaviruses Manipulate Autophagy Flux To Restrain Host Innate Immune Responses

Hantavirus is the world's most widely distributed,highly transmitted and extremely serious hemorrhagic fever virus belonging to the Hanaviridae family of Bunyavirales,an enveloped single-negative-strand RNA virus.The hantaviral genome is composed of three negative-sense genomic RNA segments,namely,S,M,and L,encoding nucleocapsid protein(NP),glycoprotein precursor(GPC),and viral RNA-dependent RNA polymerase(Rd Rp),the L fragment is the most conservative.Hantaviruses are transmitted by rodents and can cause two kinds of viral hemorrhagic diseases in humans with prominent vascular permeability defects,namely,Hantavirus Pulmonary Syndrome(HPS)and Renal Syndrome Hemorrhagic Fever(HFRS).China is the country with the highest incidence of HFRS in the world.Autophagy is an evolutionarily highly catabolic pathway in eukaryotic cells.Autophagy is closely related to various physiological and pathological processes such as cell differentiation and development,nutrient deprivation,and microbial infection.It maintains intracellular environmental stability and promotes pathogen clearance.Play an important role.Type I interferon(IFN)plays an important role in the body's antiviral innate immune response,and it can induce a variety of antiviral proteins via a variety of viral recognition receptors,linker molecules,protein kinases,and transcription factor regulatory signaling pathways.produce.Studies have reported that autophagy induced by viral infection plays an important role in the body's defense against viral invasion.It can affect the life cycle of the virus by selectively degrading viral components,and can also promote IFN production by interacting with pattern recognition receptors(PRRs).Initiate the body's innate immune response.In this study,we demonstrate that HTNV dynamically regulates the host autophagy process,triggering complete mitophagy at the early stage of infection but incomplete autophagy at the late stage.Previous research has identified that Gn-induced complete autophagy assists hantaviral replication,while the detailed mechanism is unclear(Hussein et al.,2012).Here,we found that the Gn of HTNV interacts with the Tu translation elongation factor mitochondrial(TUFM)and recruits LC3 B,promoting mitophagy-mediated degradation of MAVS and preventing the IFN responses at the early infection stage.Additionally,as an indispensable integral component of the virion,how Gn escapes autophagic clearance.Our data indicate that at the late infection stage,NP competes with Gn for binding to LC3 B,which inhibits Gn-mediated autophagosome formation,and interacts with the synaptosome-associated protein 29(SNAP29),which prevents SNARE protein-mediated autophagosome-lysosome fusion.Hence,NP disturbs autophagic degradation of Gn,expediting viral packaging and propagation.Furthermore,we also demonstrate that inhibiting autophagy process at the early stage can enhance host IFN responses and restrict HTNV replication both in vivo and in vitro.These results provide a novel virus-host interaction pattern in which the host autophagy flux is dynamically and precisely modulated by viruses for their own benefit.