SARS-CoV-2 helicase NSP13 hijacks the host protein EWSR1 to promote viral replication by enhancing RNA unwinding activity

Hongxiang Zeng; Xiang Gao; Gang Xu; Shengyuan Zhang; Lin Cheng; Tongyang Xiao; Wenhong Zu; Zheng Zhang

doi:10.1016/j.imj.2021.12.004

SARS-CoV-2 helicase NSP13 hijacks the host protein EWSR1 to promote viral replication by enhancing RNA unwinding activity

Infect Med (Beijing). 2022 Feb 24;1(1):7-16. doi: 10.1016/j.imj.2021.12.004. eCollection 2022 Mar.

Authors

Hongxiang Zeng¹, Xiang Gao¹, Gang Xu¹, Shengyuan Zhang¹, Lin Cheng¹, Tongyang Xiao¹, Wenhong Zu¹, Zheng Zhang^{1

2

3}

Affiliations

¹ Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, the Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province, China.
² Shenzhen Research Center for Communicable Disease Diagnosis and Treatment of Chinese Academy of Medical Science, Shenzhen, Guangdong Province, China.
³ Guangdong Key Laboratory for Anti-Infection Drug Quality Evaluation, Shenzhe, Guangdong Province, China.

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and has led to a global coronavirus disease 2019 (COVID-19) pandemic. Currently, incomplete understanding of how SARS-CoV-2 arrogates the host cell to establish its life cycle has led to slow progress in the development of effective drugs.

Results: In this study, we found that SARS-CoV-2 hijacks the host protein EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) to promote the activity of its helicase NSP13 to facilitate viral propagation. NSP13 is highly conserved among coronaviruses and is crucial for virus replication, providing chemical energy to unwind viral RNA replication intermediates. Treatment with different SARS-CoV-2 NSP13 inhibitors in multiple cell lines infected with SARS-CoV-2 effectively suppressed SARS-CoV-2 infection. Using affinity-purification mass spectrometry, the RNA binding protein EWSR1 was then identified as a potent host factor that physically associated with NSP13. Furthermore, silencing EWSR1 dramatically reduced virus replication at both viral RNA and protein levels. Mechanistically, EWSR1 was found to bind to the NTPase domain of NSP13 and potentially enhance its dsRNA unwinding ability.

Conclusions: Our results pinpoint EWSR1 as a novel host factor for NSP13 that could potentially be used for drug repurposing as a therapeutic target for COVID-19.

Keywords: Ewsr1; Nsp13; Unwinding.