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
  • 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: [email protected].
  • 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: [email protected].
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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