Abstract
Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot, and mouth disease (HFMD) in children. Its infection can lead to severe neurological diseases or even death in some cases. While being produced in a large quantity during infection, viral proteins often require the assistance from cellular chaperones for proper folding. In this study, we found that heat shock protein A6 (HSPA6), whose function in viral life cycle is scarcely studied, was induced and functioned as a positive regulator for EV-A71 infection. Depletion of HSPA6 led to the reductions of EV-A71 viral proteins, viral RNA and virions as a result of the downregulation of internal ribosomal entry site (IRES)-mediated translation. Unlike other HSP70 isoforms such as HSPA1, HSPA8, and HSPA9, which regulate all phases of the EV-A71 life, HSPA6 was required for the IRES-mediated translation only. Unexpectedly, the importance of HSPA6 in the IRES activity could be observed in the absence of viral proteins, suggesting that HSPA6 facilitated IRES activity through cellular factor(s) instead of viral proteins. Intriguingly, the knockdown of HSPA6 also caused the reduction of luciferase activity driven by the IRES from coxsackievirus A16, echovirus 9, encephalomyocarditis virus, or hepatitis C virus, supporting that HSPA6 may assist the function of a cellular protein generally required for viral IRES activities.
Highlights
The enterovirus A71 (EV-A71) belongs to the genus Enterovirus in the family Picornaviridae
We have reported that HSP70 family proteins, including HSPA1, HSPA8 and HSPA9, played positive roles in EV-A71 life cycle (Su et al, 2020)
We found that HSPA1, HSPA8 and HSPA9, three major members of HSP70, play multiple functions in the EV-A71 life cycle (Su et al, 2020)
Summary
The enterovirus A71 (EV-A71) belongs to the genus Enterovirus in the family Picornaviridae. The genomic RNA, functioning as the mRNA, is HSPA6 Enhances EV-A71 IRES immediately translated into a polyprotein, which is processed into 10 different viral proteins including viral RNA polymerase 3Dpol by viral proteases 2Apro, 3Cpro, and 3CDpro. The 3Dpol directs the synthesis of both genomic and antigenomic RNA in a membrane-associated replication complex containing viral proteins or their precursors including 2BC, 2B, 2C, 3A, and 3CDpro as well as host proteins (Ilnytska et al, 2013; Paul and Wimmer, 2015; van der Schaar et al, 2016). The newly synthesized genomic RNA is packaged into viral particles followed by a maturation process (Basavappa et al, 1994). Most assembled virions are released upon cell lysis as a result of the viral protein-induced apoptosis (Cong et al, 2016; Li et al, 2017); on the other hand, a small portion of the virions can be released via membrane-bound vesicles in a non-lytic manner (Feng et al, 2013; Bird et al, 2014; Robinson et al, 2014; Chen et al, 2015; Too et al, 2016)
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