SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor
Cuiling Zhang, Qiwei Jiang, Zirui Liu, Nan Li, Zhuo Hao, Gaojie Song, Dapeng Li, Minghua Chen, Lisen Lin, Yan Liu, Xiao Li, Chao Shang, Yiquan Li
Journal of Virology, doi:10.1128/jvi.00754-24
Autophagy is a cellular self-defense mechanism by which cells can kill invading pathogenic microorganisms and increase the presentation of components of pathogens as antigens. Contrarily, pathogens can utilize autophagy to enhance their own replication. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP6 can interact with ATPase proton pump component to inhibit lysosomal acidification, which was implicated in the autophagy process. However, research on how SARS-CoV-2 NSP6 affected autophagy, and its impact on virus replication is still lacking. Coronavirus NSP6 has been reported to promote coronavirus replication by limiting autophagosome expansion. However, this finding has not been confirmed in coronavirus disease 2019 . We investigated the effect of NSP6 protein on autophagosomes in differ ent mutant strains of SARS-CoV-2 and revealed that the size of autophagosomes was reduced by NSP6 of the wild-type and Delta variant of SARS-CoV-2. In addition, we found that SARS-CoV-2 NSP6 localized to the lysosome and had an inhibitory effect on the binding of autophagosomes to the lysosome, which blocked the autophagy flux; this may be related to endoplasmic reticulum (ER)-related pathways. We also found that sigma-1 receptor (SIGMAR1) knock out (KO) reversed NSP6-induced autophagosome abnormality and resisted SARS-CoV-2 infection, which responds to the fact that SIGMAR1 is likely to be used as a potential target for the treatment of SARS-CoV-2 infection. In summary, we have provided a preliminary explanation of the effects on autophagy of the SARS-CoV-2 NSP6 protein from the pre-autophagic and late stages, and also found that SIGMAR1 is likely to be used as a potential target for SARS-CoV-2 therapy to develop relevant drugs. IMPORTANCE We have provided a preliminary explanation of the effects on autoph agy of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structure protein 6 from the pre-autophagic and late stages, and also found that sigma-1 receptor is likely to be used as a potential target for SARS-CoV-2 therapy to develop relevant drugs.
AUTHOR AFFILIATIONS
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Supplemental Material Supplemental figures (JVI00754-24-s0001.pdf). Figures S1 to S5.
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' <jats:sec>\n'
' <jats:title/>\n'
' <jats:p>Autophagy is a cellular self-defense mechanism by which cells can kill '
'invading pathogenic microorganisms and increase the presentation of components of pathogens '
'as antigens. Contrarily, pathogens can utilize autophagy to enhance their own replication. '
'Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP6 can interact with ATPase '
'proton pump component to inhibit lysosomal acidification, which was implicated in the '
'autophagy process. However, research on how SARS-CoV-2 NSP6 affected autophagy, and its '
'impact on virus replication is still lacking. Coronavirus NSP6 has been reported to promote '
'coronavirus replication by limiting autophagosome expansion. However, this finding has not '
'been confirmed in coronavirus disease 2019 (COVID-19). We investigated the effect of NSP6 '
'protein on autophagosomes in different mutant strains of SARS-CoV-2 and revealed that the '
'size of autophagosomes was reduced by NSP6 of the wild-type and Delta variant of SARS-CoV-2. '
'In addition, we found that SARS-CoV-2 NSP6 localized to the lysosome and had an inhibitory '
'effect on the binding of autophagosomes to the lysosome, which blocked the autophagy flux; '
'this may be related to endoplasmic reticulum (ER)-related pathways. We also found that '
'sigma-1 receptor (SIGMAR1) knock out (KO) reversed NSP6-induced autophagosome abnormality and '
'resisted SARS-CoV-2 infection, which responds to the fact that SIGMAR1 is likely to be used '
'as a potential target for the treatment of SARS-CoV-2 infection. In summary, we have provided '
'a preliminary explanation of the effects on autophagy of the SARS-CoV-2 NSP6 protein from the '
'pre-autophagic and late stages, and also found that SIGMAR1 is likely to be used as a '
'potential target for SARS-CoV-2 therapy to develop relevant drugs.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>IMPORTANCE</jats:title>\n'
' <jats:p>We have provided a preliminary explanation of the effects on autophagy of '
'the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structure protein 6 from '
'the pre-autophagic and late stages, and also found that sigma-1 receptor is likely to be used '
'as a potential target for SARS-CoV-2 therapy to develop relevant drugs.</jats:p>\n'
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