West Nile virus capsid protein inhibits autophagy by AMP-activated protein kinase degradation in neurological disease development
Autoři:
Shintaro Kobayashi aff001; Kentaro Yoshii aff001; Wallaya Phongphaew aff002; Memi Muto aff001; Minato Hirano aff001; Yasuko Orba aff002; Hirofumi Sawa aff002; Hiroaki Kariwa aff001
Působiště autorů:
Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan
aff001; Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
aff002; Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan
aff003; Global Virus Network, Baltimore, Maryland, United States of America
aff004
Vyšlo v časopise:
West Nile virus capsid protein inhibits autophagy by AMP-activated protein kinase degradation in neurological disease development. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008238
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.ppat.1008238
Souhrn
West Nile virus (WNV) belongs to the Flaviviridae family and has emerged as a significant cause of viral encephalitis in birds and animals including humans. WNV replication directly induces neuronal injury, followed by neuronal cell death. We previously showed that accumulation of ubiquitinated protein aggregates was involved in neuronal cell death in the WNV-infected mouse brain. In this study, we attempted to elucidate the mechanisms of the accumulation of protein aggregates in the WNV-infected cells. To identify the viral factor inducing the accumulation of ubiquitinated proteins, intracellular accumulation of ubiquitinated proteins was examined in the cells expressing the viral protein. Expression of capsid (C) protein induced the accumulation, while mutations at residues L51 and A52 in C protein abrogated the accumulation. Wild-type (WT) or mutant WNV in which mutations were introduced into the residues was inoculated into human neuroblastoma cells. The expression levels of LC3-II, an autophagy-related protein, and AMP-activated protein kinase (AMPK), an autophagy inducer, were reduced in the cells infected with WT WNV, while the reduction was not observed in the cells infected with WNV with the mutations in C protein. Similarly, ubiquitination and degradation of AMPK were only observed in the cells infected with WT WNV. In the cells expressing C protein, AMPK was co-precipitated with C protein and mutations in L51 and A52 reduced the interaction. Although the viral replication was not affected, the accumulation of ubiquitinated proteins in brain and neurological symptoms were attenuated in the mouse inoculated with WNV with the mutations in C protein as compared with that with WT WNV. Taken together, ubiquitination and degradation of AMPK by C protein resulted in the inhibition of autophagy and the accumulation of protein aggregates, which contributes to the development of neurological disease.
Klíčová slova:
Autophagic cell death – Cell staining – DAPI staining – Immunoblotting – Neuronal death – Plasmid construction – Protein expression – West Nile virus
Zdroje
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