Heat Shock protein 90: Role in Enterovirus 71 Entry and Assembly and Potential Target for Therapy

Abstract

Although several factors participating in enterovirus 71 (EV71) entry and replication had been reported, the precise mechanisms associated with these events are far from clear. In the present study, we showed that heat shock protein 90 (HSP90) is a key element associated with EV71 entry and replication in a human rhabdomyosarcoma of RD cells. Inhibition of HSP90 by pretreating host cells with HSP90β siRNA or blocking HSP90 with a HSP90-specific antibody or geldanamycin (GA), a specific inhibitor of HSP90, as well as recombinant HSP90β resulted in inhibiting viral entry and subsequent viral replication. Co-immunprecipitation of EV71 with recombinant HSP90β and colocalization of EV71-HSP90 in the cells demonstrated that HSP90 was physically associated with EV71 particles. HSP90 seems to mediate EV71 replication by preventing proteosomal degradation of the newly synthesized capsid proteins, but does not facilitate viral gene expression at transcriptional level. This was evident by post-treatment of host cells with GA, which did not affect the expression of viral transcripts but accelerated the degradation of viral capsid proteins and interfered with the formation of assembled virions. In vivo studies were carried out using human SCARB2-transgenic mice to evaluate the protection conferred by HSP90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), an analog of geldanamycin, that elicited similar activity but with less toxicity. The results showed that the administration of 17-AAG twice conferred the resistance to hSCARB2 mice challenged with C2, C4, and B4 genotypes of EV71. Our data supports HSP90 plays an important role in EV71 infection. Targeting of HSP90 with clinically available drugs might provide a feasible therapeutic approach to treat EV71 infection.

The life cycle of non-polio enteroviruses and how to target it

“…Enterovirus assembly can be inhibited by geldanamycin 105 , an HSP90 inhibitor, but this inhibitor has cytotoxic effects and has mainly been investigated for its antitumour activity. Glutathione levels can be manipulated in several ways, but this is unlikely to be an effective antiviral strategy because only a subset of enteroviruses depends on glutathione for efficient assembly 99,100,106 .…”

Human Enterovirus Group B Viruses Rely on Vimentin Dynamics for Efficient Processing of Viral Nonstructural Proteins

“…Heat shock proteins (Hsps), and Hsp70 in particular, have been associated with several virus infections, such as rabies (41) and dengue (42). Hsp90 was previously shown to be essential for the viral assembly and capsid production of enterovirus 71 (43) and poliovirus (44) by protecting the viral components from proteasomal degradation. Here, we wanted to determine whether Hsp70 and Hsp90 had any role in vimentin dynamics during infection.…”

Inhibition of heat shock protein 90 suppresses Bombyx mori nucleopolyhedrovirus replication in B. mori

“…On the one hand, viruses, as obligate parasites, require host factors for their efficient replication . Hsp90 promotes viral infection in different stages of the viral life cycle by interactions with critical viral factors including capsid proteins, DNA polymerase, virus RNA complexes and nonstructural proteins (Kawashima et al, 2013;Rathore et al, 2014;Tsou et al, 2013;Vashist et al, 2015). On the other hand, Hsp90 can interact with host factors to regulate the host immune response and proliferation or apoptosis of virus-infected cells (Citri et al, 2006;Jeon et al, 2010;Lee et al, 2013).…”