Rabies Virus Infection Induces Microtubule Depolymerization to Facilitate Viral RNA Synthesis by Upregulating HDAC6.

Jie Zan,Bo-Li Hu,Dong-Nan Sun,Yan Yan,Min Liao,Ji-Yong Zhou,Kai-Kun Mo,Song Liu,Jin-Yan Gu,Juan Liu

doi:10.3389/fcimb.2017.00146

Abstract

Rabies virus (RABV) is the cause of rabies, and is associated with severe neurological symptoms, high mortality rate, and a serious threat to human health. Although cellular tubulin has recently been identified to be incorporated into RABV particles, the effects of RABV infection on the microtubule cytoskeleton remain poorly understood. In this study, we show that RABV infection induces microtubule depolymerization as observed by confocal microscopy, which is closely associated with the formation of the filamentous network of the RABV M protein. Depolymerization of microtubules significantly increases viral RNA synthesis, while the polymerization of microtubules notably inhibits viral RNA synthesis and prevents the viral M protein from inducing the formation of the filamentous network. Furthermore, the histone deacetylase 6 (HDAC6) expression level progressively increases during RABV infection, and the inhibition of HDAC6 deacetylase activity significantly decreases viral RNA synthesis. In addition, the expression of viral M protein alone was found to significantly upregulate HDAC6 expression, leading to a substantial reduction in its substrate, acetylated α-tubulin, eventually resulting in microtubule depolymerization. These results demonstrate that HDAC6 plays a positive role in viral transcription and replication by inducing microtubule depolymerization during RABV infection.

Highlights

Rabies virus (RABV) is a prototypical member of the Lyssavirus genus of the Rhabdoviridae family, and the causative agent of rabies
Similar results were obtained with the BHK-21 and 293T cells (Supplementary Figure 2). These results indicate that RABV infection damages the host microtubule cytoskeleton and is associated with the accumulation of the viral M protein
We were the first to demonstrate that microtubule depolymerization induced by RABV infection facilitates viral RNA synthesis

Summary

Introduction

Rabies virus (RABV) is a prototypical member of the Lyssavirus genus of the Rhabdoviridae family, and the causative agent of rabies. Rabies is associated with severe neurological symptoms and high mortality rate, causing more than 50,000 human deaths annually, mainly in Asia and Africa (Sudarshan et al, 2007). Microtubule Depolarization Promotes RABV Transcription and a serious threat to human health. The life cycle of RABV occurs exclusively in the cytoplasm with the transcription of five viral genes that encode the viral proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L), respectively. The M protein has been reported to regulate the balance of viral RNA synthesis and be related to the pathogenicity of RABV (Finke and Conzelmann, 2003; Pulmanausahakul et al, 2008; Wirblich et al, 2008)

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