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

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.

Overexpression of MAP2 and NF-H Associated with Dendritic Pathology in the Spinal Cord of Mice Infected with Rabies Virus

“…A link between increased MAP2 expression and dendritic pathology in Down’s syndrome has also been established [ 37 ]. The interruption of the cytoskeleton by microtubule depolymerization is due to loss of α-tubulin caused by infection with rabies virus via the formation of an M-protein filament network [ 27 ], which confirms that rabies infection damages the cytoskeleton of the host cell and is associated with the accumulation of viral M proteins.…”

“…In contrast, Song et al did not show any qualitative variation in the immunoreactivity of MAP2 in the pyramidal neurons of the hippocampus of infected mice [ 13 ]. Other studies have shown diminished immunoreactivity of MAP2 and NF-H in neurons infected in vitro [ 11 ], as well as loss of expression of MAP2 in neurons of the cerebral cortex and cerebellar peduncle [ 26 ] and loss of actin filaments in the hippocampus of mice [ 13 ] and in cell cultures [ 27 ]. It is possible that these differences are due to the type and virulence of the viral strains used in the studies [ 26 ].…”

Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection

“…Whole cell lysates were subjected to SDS-PAGE and immunoblotting as previously described [28]. Primary antibodies against YY1 (ab109237, Abcam), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ab8245, Abcam), TBK1 (ab40676, Abcam), phosphorylated TBK1 (pTBK1) (ab109272, Abcam), IRF3 (ab68481, Abcam), phosphorylated IRF3 (pIRF3) (ab76493, Abcam), Lamin A (ab8980, Abcam), IRF9 (ab51639, Abcam), STAT1 (14994, Cell Signal Technology), phosphorylated STAT1 (pSTAT1) (9167, Cell Signal Technology), STAT2 (72604, Cell Signal Technology), phosphorylated STAT2 (pSTAT2) (ab53132, Abcam), flag (ab18230, Abcam) and Myc (ab18185, Abcam) were used.…”

The Deoptimization of Rabies Virus Matrix Protein Impacts Viral Transcription and Replication

“…Recent studies indicate that M inhibits NF-κB signaling through interactions with RelAp43 that acts to promote RABV infection [4][5][6]. The overexpression of M increases the expression of HDAC6, which increases RABV transcription and replication through microtubule depolymerization [7]. Residue 58 of M is also critical to RABV replication [8].…”