Abstract
Autophagy is an important homeostatic process for the degradation of cytosolic proteins and organelles and has been reported to play an important role in cellular responses to pathogens and virus replication. However, the role of autophagy in Coxsackievirus A16 (CA16) infection and pathogenesis remains unknown. Here, we demonstrated that CA16 infection enhanced autophagosome formation, resulting in increased extracellular virus production. Moreover, expression of CA16 nonstructural proteins 2C and 3C was sufficient to trigger autophagosome accumulation by blocking the fusion of autophagosomes with lysosomes. Interestingly, we found that Immunity-related GTPase family M (IRGM) was crucial for the activation of CA16 infection-induced autophagy; in turn, reducing IRGM expression suppressed autophagy. Expression of viral protein 2C enhanced IRGM promoter activation, thereby increasing IRGM expression and inducing autophagy. CA16 infection inhibited Akt/mTOR signaling and activated extracellular signal-regulated kinase (ERK) signaling, both of which are necessary for autophagy induction. In summary, CA16 can use autophagy to enhance its own replication. These results raise the possibility of targeting the autophagic pathway for the treatment of hand, foot, and mouth disease (HFMD).
Highlights
Coxsackievirus A16 (CA16) is a positive-strand non-enveloped RNA virus that belongs to the genus Enterovirus in the family Picornaviridae[1]
These results showed that LC3-II levels correlated well with VP1 protein expression, indicating that the autophagy was induced by CA16 infection (Fig 1A)
We report for the first time that CA16 infection increases autophagosome accumulation in HeLa cells in a manner that facilitates virus production
Summary
Coxsackievirus A16 (CA16) is a positive-strand non-enveloped RNA virus that belongs to the genus Enterovirus in the family Picornaviridae[1]. ERK activity has been reported to be associated with autophagic cell death in response to different stresses, such as amino acid depletion and virus infection [12]. Herpes simplex virus 1 (HSV-1) has been confirmed to suppress the host cell autophagy response to decrease MHC class I presentation of viral antigens[16]. Rhinovirus type 2 does not induce the synthesis of LC3-positive compartments and the modification of autophagy does not result in increased viral synthesis[19]. These discrepancies led us to investigate the function of autophagy during coxsackievirus A16 infection. We provide the first evidence that cellular autophagy is promoted in CA16-infected cells
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