Heat-shock protein 90 promotes nuclear transport of herpes simplex virus 1 capsid protein by interacting with acetylated tubulin.

Meigong Zhong,Maoyun Chen,Yangfei Xiang,Kaiqi Ma,Yifei Wang,Qiaoli Wang,Xianxiu Qiu,Fujun Jin,Kai Zheng,Tao Peng,Kaio Kitazato

doi:10.1371/journal.pone.0099425

Abstract

Although it is known that inhibitors of heat shock protein 90 (Hsp90) can inhibit herpes simplex virus type 1 (HSV-1) infection, the role of Hsp90 in HSV-1 entry and the antiviral mechanisms of Hsp90 inhibitors remain unclear. In this study, we found that Hsp90 inhibitors have potent antiviral activity against standard or drug-resistant HSV-1 strains and viral gene and protein synthesis are inhibited in an early phase. More detailed studies demonstrated that Hsp90 is upregulated by virus entry and it interacts with virus. Hsp90 knockdown by siRNA or treatment with Hsp90 inhibitors significantly inhibited the nuclear transport of viral capsid protein (ICP5) at the early stage of HSV-1 infection. In contrast, overexpression of Hsp90 restored the nuclear transport that was prevented by the Hsp90 inhibitors, suggesting that Hsp90 is required for nuclear transport of viral capsid protein. Furthermore, HSV-1 infection enhanced acetylation of α-tubulin and Hsp90 interacted with the acetylated α-tubulin, which is suppressed by Hsp90 inhibition. These results demonstrate that Hsp90, by interacting with acetylated α-tubulin, plays a crucial role in viral capsid protein nuclear transport and may provide novel insight into the role of Hsp90 in HSV-1 infection and offer a promising strategy to overcome drug-resistance.

Highlights

Herpes simplex virus type 1 (HSV-1) is a member of the Herpesviridae family [1]
By over-expressing of GFP-fused heat shock protein 90 (Hsp90) in cells, we still found that GFP-Hsp90 was directly associated with viral ICP5 protein. These results demonstrated that HSV-1 infection induces Hsp90 upregulation and nuclear translocation, which interacts with ICP5, suggesting Hsp90 is involved in the nuclear transport of viral capsid protein ICP5
More recent research has indicated that HSV-1 ICP5, the major capsid protein can interact with the dynein light chain, this putative interaction needs to be confirmed in infected cells [30]

Summary

Introduction

Herpes simplex virus type 1 (HSV-1) is a member of the Herpesviridae family [1]. The HSV-1 virion consists of a relatively large, double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid [2]. HSV-1 has mainly oral and ocular manifestations, and after primary infection, the virus can establish latency in the trigeminal or cervical ganglia. The latent virus can be reactivated to induce neurite damage and neuronal death. The currently available anti-HSV drugs are mainly nucleoside analogs, such as acyclovir (ACV), and all of them target viral DNA replication. Drug-resistant HSV strains, and ACV-resistant HSV strains, emerge frequently [3,4]. The development of new anti-HSV agents with different mechanisms of action is a matter of great urgency

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Results

Conclusion