Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load

Yasen Maimaitiyiming; Tao Yang; Qian Qian Wang; Yan Feng; Zhi Chen; Mikael Björklund; Fudi Wang; Chonggao Hu; Chih-Hung Hsu; Hua Naranmandura

doi:10.34133/2022/9802969

Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load

Research (Wash D C). 2022 Feb 23:2022:9802969. doi: 10.34133/2022/9802969. eCollection 2022.

Authors

Yasen Maimaitiyiming^{1

2

3}, Tao Yang^{1

2}, Qian Qian Wang^{1

2}, Yan Feng⁴, Zhi Chen⁵, Mikael Björklund⁶, Fudi Wang^{7

8}, Chonggao Hu⁴, Chih-Hung Hsu⁹, Hua Naranmandura^{1

2}

Affiliations

¹ Department of Public Health and Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
² Zhejiang University Cancer Center, Hangzhou 310058, China.
³ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China.
⁴ Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China.
⁵ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining 314499, Zhejiang, China.
⁷ The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁸ Hengyang Medical School, University of South China, Hengyang 421001, China.
⁹ Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China.

Abstract

Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., 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. Multiple 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 as 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 treatment maintains low levels of both wild-type and P323L mutant of NSP12, suggesting clinical potential. Collectively, this novel mechanism, heat-induced NSP12 degradation, suggests a prospective heat-based intervention against SARS-CoV-2.