SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation

Dianqi Zhang; Likai Ji; Xu Chen; Yumin He; Yijie Sun; Li Ji; Tiancheng Zhang; Quan Shen; Xiaochun Wang; Yan Wang; Shixing Yang; Wen Zhang; Chenglin Zhou

doi:10.1016/j.isci.2023.107705

SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation

iScience. 2023 Aug 23;26(9):107705. doi: 10.1016/j.isci.2023.107705. eCollection 2023 Sep 15.

Authors

Dianqi Zhang^{1

2

3}, Likai Ji², Xu Chen^{2

4}, Yumin He^{2

5}, Yijie Sun², Li Ji², Tiancheng Zhang², Quan Shen², Xiaochun Wang², Yan Wang², Shixing Yang^{1

2}, Wen Zhang^{1

2}, Chenglin Zhou¹

Affiliations

¹ Clinical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China.
² Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
³ Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214221, China.
⁴ Department of Laboratory Medicine and Pathology, Jiangsu Provincial Corps Hospital of Chinese People's Armed Police Force, Yangzhou, Jiangsu 225003, China.
⁵ Medical Research Center, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225001, China.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes 2019 coronavirus disease (COVID-19), poses a significant threat to global public health security. Like other coronaviruses, SARS-CoV-2 has developed various strategies to inhibit the production of interferon (IFN). Here, we have discovered that SARS-CoV-2 Nsp15 obviously reduces the expression of IFN-β and IFN-stimulated genes (ISG56, CXCL10), and also inhibits IRF3 phosphorylation and nuclear translocation by antagonizing the RLR-mediated antiviral signaling pathway. Mechanically, we found that the poly-U-specific endonuclease domain (EndoU) of Nsp15 directly associates with the kinase domain (KD) of TBK1 to interfere TBK1 interacting with IRF3 and the flowing TBK1-mediated IRF3 phosphorylation. Furthermore, Nsp15 also prevented nuclear translocation of phosphorylated IRF3 via binding to the nuclear import adaptor karyopherin α1 (KPNA1) and promoting it autophagy-dependent degradation. These findings collectively reveal a novel mechanism by which Nsp15 antagonizes host's innate immune response.

Keywords: Cell biology; Immunology; Virology.