The NS2B-PP1α-eIF2α axis: Inhibiting stress granule formation and Boosting Zika virus replication.

Autor: Wu X; State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China., Zhang L; College of Life Sciences, Hubei University, Wuhan, China., Liu C; State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China., Cheng Q; Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China., Zhao W; Tissue Engineering and Organ Manufacturing (TEOM) lab, Department of Biomedical Engineering, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, China., Chen P; Tissue Engineering and Organ Manufacturing (TEOM) lab, Department of Biomedical Engineering, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, China.; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China., Qin Y; State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.; College of Life Sciences, Hubei University, Wuhan, China., Chen M; State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.; College of Life Sciences, Hubei University, Wuhan, China.; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.; Hubei Jiangxia Laboratory, Wuhan, China.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Jun 27; Vol. 20 (6), pp. e1012355. Date of Electronic Publication: 2024 Jun 27 (Print Publication: 2024).
DOI: 10.1371/journal.ppat.1012355
Abstrakt: Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference without clear understanding. This study reveals the role of Zika virus (ZIKV) NS2B as a scaffold protein mediating interaction between protein phosphatase 1α (PP1α) and eukaryotic initiation factor 2α (eIF2α). This interaction promotes eIF2α dephosphorylation by PP1α, inhibiting SG formation. The NS2B-PP1α complex exhibits remarkable stability, resisting ubiquitin-induced degradation and amplifying eIF2α dephosphorylation, thus promoting ZIKV replication. In contrast, the NS2BV35A mutant, interacting exclusively with eIF2α, fails to inhibit SG formation, resulting in reduced viral replication and diminished impact on brain organoid growth. These findings reveal PP1α's dual role in ZIKV infection, inducing interferon production as an antiviral factor and suppressing SG formation as a viral promoter. Moreover, we found that NS2B also serves as a versatile mechanism employed by flaviviruses to counter host antiviral defenses, primarily by broadly inhibiting SG formation. This research advances our comprehension of the complex interplay in flavivirus-host interactions, offering potential for innovative therapeutic strategies against flavivirus infections.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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