Despite extensive eforts,COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large.Vaccination is an eftive approach to curb virus spread,but several variants(eg.delta,delta plus,omicron,and IHU)appear to wea...Despite extensive eforts,COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large.Vaccination is an eftive approach to curb virus spread,but several variants(eg.delta,delta plus,omicron,and IHU)appear to weaken or possibly escape immune protection.Thus,novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed.Mutiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism.Here.we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase(also known a nonstructural protein 12(NSP12))of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants,including omicron and IHU.Mechanistically,heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer.A mild daily heat Ireatment maintains low levels of both wild-type and P323L mutant of NSP12,sugesting clinical potential.Collctivel',this novel mechanism,heat-induced NSP12 degradation,suggests a prospective heat-based intervention against SARS-CoV-2.展开更多
基金supported by grants from the Zhejiang Provincial Natural Science Foundation of China(LD22H310005)the National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX10302-206)+3 种基金the National Key R&D Program of China(2021YFC2700903)the National Natural Science Foundation of China(Nos.81872942,82000155,82003875,and 31972883)the China Postdoctoral Science Foundation(No.2021M702877)and the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.
文摘Despite extensive eforts,COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large.Vaccination is an eftive approach to curb virus spread,but several variants(eg.delta,delta plus,omicron,and IHU)appear to weaken or possibly escape immune protection.Thus,novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed.Mutiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism.Here.we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase(also known a nonstructural protein 12(NSP12))of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants,including omicron and IHU.Mechanistically,heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer.A mild daily heat Ireatment maintains low levels of both wild-type and P323L mutant of NSP12,sugesting clinical potential.Collctivel',this novel mechanism,heat-induced NSP12 degradation,suggests a prospective heat-based intervention against SARS-CoV-2.
