2. Academic Validation
  3. SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α

SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α

  • Cell Signal. 2024 Sep 7:124:111387. doi: 10.1016/j.cellsig.2024.111387.
Xiaoli Mou 1,  Fan Luo 2,  Weihao Zhang 3,  Qi Cheng 3,  Jussi Hepojoki 4,  Shaowei Zhu 3,  Yuanyuan Liu 3,  Hairong Xiong 3,  Deyin Guo 5,  Jingyou Yu 5,  Liangjun Chen 6,  Yirong Li 6,  Wei Hou 7,  Shuliang Chen 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei 430071, China; Guangzhou Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China.
  • 2 State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei 430071, China; Department of Virology, Faculty of Medicine, Medicum, University of Helsinki, 00290 Helsinki, Finland.
  • 3 State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei 430071, China.
  • 4 Department of Virology, Faculty of Medicine, Medicum, University of Helsinki, 00290 Helsinki, Finland.
  • 5 Guangzhou Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China.
  • 6 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
  • 7 State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei 430071, China; School of Public Health, Wuhan University, Wuhan, Hubei 430071, China; School of Ecology and Environment, Tibet University, Lhasa, Tibet 850000, China; Shenzhen Research Institute, Wuhan University, Shenzhen, Guangdong 518057, China. Electronic address: houwei@whu.edu.cn.
  • 8 State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan, Hubei 430071, China. Electronic address: chen-shuliang@whu.edu.cn.
PMID: 39251053 DOI: 10.1016/j.cellsig.2024.111387
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1α (HIF-1α) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1α, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1α, thereby inhibiting ubiquitin-dependent degradation of HIF-1α and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1α expression, which in turn exacerbates the production of IL-6.

Keywords

HIF-1α; IL-6; NSP16; SARS-CoV-2; Ubiquitination.

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