Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism

Author:

Yuan Yueming12,Fang An12,Wang Haoran12,Wang Caiqian12,Sui Baokun12,Zhao Jianqing12,Fu Zhen F.12,Zhou Ming12ORCID,Zhao Ling1234ORCID

Affiliation:

1. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China

2. Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China

3. Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China

4. Hubei Hongshan Laboratory, Wuhan, China

Abstract

ABSTRACT Infection with neurotropic viruses may result in changes in host behavior, which are closely associated with degenerative changes in neurons. The lyssavirus genus comprises highly neurotropic viruses, including the rabies virus (RABV), which has been shown to induce degenerative changes in neurons, marked by the self-destruction of axons. The underlying mechanism by which the RABV degrades neuronal cytoskeletal proteins remains incomplete. In this study, we show that infection with RABV or overexpression of its M protein can disrupt mitochondrial metabolism by binding to Slc25a4. This leads to a reduction in NAD + production and a subsequent influx of Ca 2+ from the endoplasmic reticulum and mitochondria into the cytoplasm of neuronal cell lines, activating Ca 2+ -dependent proteinase calpains that degrade α-tubulin. We further screened the M proteins of different lyssaviruses and discovered that the M protein of the dog-derived RABV strain (DRV) does not degrade α-tubulin. Sequence analysis of the DRV M protein and that of the lab-attenuated RABV strain CVS revealed that the 57th amino acid is vital for M-induced microtubule degradation. We generated a recombinant RABV with a mutation at the 57th amino acid position in its M protein and showed that this mutation reduces α-tubulin degradation in vitro and axonal degeneration in vivo . This study elucidates the mechanism by which lyssavirus induces neuron degeneration. IMPORTANCE Previous studies have suggested that RABV (rabies virus, the representative of lyssavirus) infection induces structural abnormalities in neurons. But there are few articles on the mechanism of lyssavirus’ effect on neurons, and the mechanism of how RABV infection induces neurological dysfunction remains incomplete. The M protein of lyssavirus can downregulate cellular ATP levels by interacting with Slc25a4, and this decrease in ATP leads to a decrease in the level of NAD + in the cytosol, which results in the release of Ca 2+ from the intracellular calcium pool, the endoplasmic reticulum, and mitochondria. The presence of large amounts of Ca 2+ in the cytoplasm activates Ca 2+ -dependent proteases and degrades microtubule proteins. The amino acid 57 of M protein is the key site determining its disruption of mitochondrial metabolism and subsequent neuron degeneration.

Funder

MOST | National Key Research and Development Program of China

MOE | Fundamental Research Funds for the Central Universities

Publisher

American Society for Microbiology

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