tetano
Editor, Senior Moderator
Cell Death Differ
. 2022 Jan 8.
doi: 10.1038/s41418-021-00916-7. Online ahead of print.
SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1
Xiao Sun[SUP] 1 2 [/SUP], Yingzhi Liu[SUP] 2 [/SUP], Ziheng Huang[SUP] 2 [/SUP], Wenye Xu[SUP] 3 [/SUP], Wei Hu[SUP] 4 [/SUP], Lina Yi[SUP] 5 [/SUP], Zhe Liu[SUP] 5 [/SUP], Hung Chan[SUP] 2 [/SUP], Judeng Zeng[SUP] 2 [/SUP], Xiaodong Liu[SUP] 2 [/SUP], Huarong Chen[SUP] 2 6 7 8 [/SUP], Jun Yu[SUP] 2 6 7 8 [/SUP], Francis Ka Leung Chan[SUP] 2 6 7 [/SUP], Siew Chien Ng[SUP] 2 6 7 [/SUP], Sunny Hei Wong[SUP] 2 6 7 9 [/SUP], Maggie Haitian Wang[SUP] 8 10 [/SUP], Tony Gin[SUP] 2 [/SUP], Gavin Matthew Joynt[SUP] 2 [/SUP], David Shu Cheong Hui[SUP] 3 [/SUP], Xuan Zou[SUP] 11 [/SUP], Yuelong Shu[SUP] 12 [/SUP], Christopher Hon Ki Cheng[SUP] 1 [/SUP], Shisong Fang[SUP] 13 [/SUP], Huanle Luo[SUP] 14 [/SUP], Jing Lu[SUP] 15 [/SUP], Matthew Tak Vai Chan[SUP] 16 [/SUP], Lin Zhang[SUP] 17 18 19 [/SUP], William Ka Kei Wu[SUP] 20 21 22 23 [/SUP]
Affiliations
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 D[SUB]3[/SUB], 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.
. 2022 Jan 8.
doi: 10.1038/s41418-021-00916-7. Online ahead of print.
SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1
Xiao Sun[SUP] 1 2 [/SUP], Yingzhi Liu[SUP] 2 [/SUP], Ziheng Huang[SUP] 2 [/SUP], Wenye Xu[SUP] 3 [/SUP], Wei Hu[SUP] 4 [/SUP], Lina Yi[SUP] 5 [/SUP], Zhe Liu[SUP] 5 [/SUP], Hung Chan[SUP] 2 [/SUP], Judeng Zeng[SUP] 2 [/SUP], Xiaodong Liu[SUP] 2 [/SUP], Huarong Chen[SUP] 2 6 7 8 [/SUP], Jun Yu[SUP] 2 6 7 8 [/SUP], Francis Ka Leung Chan[SUP] 2 6 7 [/SUP], Siew Chien Ng[SUP] 2 6 7 [/SUP], Sunny Hei Wong[SUP] 2 6 7 9 [/SUP], Maggie Haitian Wang[SUP] 8 10 [/SUP], Tony Gin[SUP] 2 [/SUP], Gavin Matthew Joynt[SUP] 2 [/SUP], David Shu Cheong Hui[SUP] 3 [/SUP], Xuan Zou[SUP] 11 [/SUP], Yuelong Shu[SUP] 12 [/SUP], Christopher Hon Ki Cheng[SUP] 1 [/SUP], Shisong Fang[SUP] 13 [/SUP], Huanle Luo[SUP] 14 [/SUP], Jing Lu[SUP] 15 [/SUP], Matthew Tak Vai Chan[SUP] 16 [/SUP], Lin Zhang[SUP] 17 18 19 [/SUP], William Ka Kei Wu[SUP] 20 21 22 23 [/SUP]
Affiliations
- PMID: 34997207
- DOI: 10.1038/s41418-021-00916-7
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 D[SUB]3[/SUB], 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.