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Title: SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1
Authors: Sun, Xiao
Liu, Yingzhi
Huang, Ziheng
Xu, Wenye
Hu, Wei
Yi, Lina
Liu, Zhe
Chan, Hung
Zeng, Judeng
Liu, Xiaodong
Chen, Huarong
Yu, Jun
Chan, Francis Ka Leung
Ng, Siew Chien
Wong, Sunny Hei
Wang, Maggie Haitian
Gin, Tony
Joynt, Gavin Matthew
Hui, David Shu Cheong
Zou, Xuan
Shu, Yuelong
Cheng, Christopher Hon Ki
Fang, Shisong
Luo, Huanle
Lu, Jing
Chan, Matthew Tak Vai
Zhang, Lin
Wu, William Ka Kei
Keywords: Science::Medicine
Issue Date: 2022
Source: Sun, X., Liu, Y., Huang, Z., Xu, W., Hu, W., Yi, L., Liu, Z., Chan, H., Zeng, J., Liu, X., Chen, H., Yu, J., Chan, F. K. L., Ng, S. C., Wong, S. H., Wang, M. H., Gin, T., Joynt, G. M., Hui, D. S. C., ...Wu, W. K. K. (2022). SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1. Cell Death and Differentiation, 29(6), 1240-1254.
Journal: Cell Death and Differentiation
Abstract: A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.
ISSN: 1350-9047
DOI: 10.1038/s41418-021-00916-7
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Rights: © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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