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Hokkaido University Collection of Scholarly and Academic Papers >
Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine >
Peer-reviewed Journal Articles, etc >
West Nile virus capsid protein inhibits autophagy by AMP-activated protein kinase degradation in neurological disease development
This item is licensed under:Creative Commons Attribution 4.0 International
| Title: | West Nile virus capsid protein inhibits autophagy by AMP-activated protein kinase degradation in neurological disease development |
| Authors: | Kobayashi, Shintaro Browse this author →KAKEN DB | | Yoshii, Kentaro Browse this author →KAKEN DB | | Phongphaew, Wallaya Browse this author | | Muto, Memi Browse this author | | Hirano, Minato Browse this author | | Orba, Yasuko Browse this author →KAKEN DB | | Sawa, Hirofumi Browse this author →KAKEN DB | | Kariwa, Hiroaki Browse this author →KAKEN DB |
| Issue Date: | Jan-2020 |
| Publisher: | PLOS |
| Journal Title: | PLoS pathogens |
| Volume: | 16 |
| Issue: | 1 |
| Start Page: | e1008238 |
| Publisher DOI: | 10.1371/journal.ppat.1008238 |
| Abstract: | 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. Author summary The elimination of ubiquitinated protein aggregates from neuronal cells occurs via protein degradation systems such as autophagy or proteasome. Previously, we determined that WNV infection induces the accumulation of ubiquitinated proteins in neuronal cells. However, the detailed mechanisms underlying this accumulation and its association with pathogenicity in the brain remain unclear. Here, we demonstrated that residues L51 and A52 of WNV C protein are responsible for the accumulation of the ubiquitinated proteins. The two C protein residues promoted the interaction between C protein and the autophagy-inducing enzyme AMPK, resulting in ubiquitination and degradation of AMPK and inhibition of autophagy. A mutation in WNV that impaired the AMPK-C protein interaction attenuated the accumulation of ubiquitinated proteins and neurological symptoms in mice. Our findings are the first to describe the regulation of AMPK by a viral protein and represent a step forward in understanding of molecular mechanisms of the neuropathogenesis of WNV infection. |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/76937 |
| Appears in Collections: | 獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 小林 進太郎
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