tetano
Editor, Senior Moderator
Cell Signal
. 2024 Sep 7:111387.
doi: 10.1016/j.cellsig.2024.111387. Online ahead of print. SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α
Xiaoli Mou[SUP] 1 [/SUP], Fan Luo[SUP] 2 [/SUP], Weihao Zhang[SUP] 3 [/SUP], Qi Cheng[SUP] 3 [/SUP], Jussi Hepojoki[SUP] 4 [/SUP], Shaowei Zhu[SUP] 3 [/SUP], Yuanyuan Liu[SUP] 3 [/SUP], Hairong Xiong[SUP] 3 [/SUP], Deyin Guo[SUP] 5 [/SUP], Jingyou Yu[SUP] 5 [/SUP], Liangjun Chen[SUP] 6 [/SUP], Yirong Li[SUP] 6 [/SUP], Wei Hou[SUP] 7 [/SUP], Shuliang Chen[SUP] 8 [/SUP]
Affiliations
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.
. 2024 Sep 7:111387.
doi: 10.1016/j.cellsig.2024.111387. Online ahead of print. SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α
Xiaoli Mou[SUP] 1 [/SUP], Fan Luo[SUP] 2 [/SUP], Weihao Zhang[SUP] 3 [/SUP], Qi Cheng[SUP] 3 [/SUP], Jussi Hepojoki[SUP] 4 [/SUP], Shaowei Zhu[SUP] 3 [/SUP], Yuanyuan Liu[SUP] 3 [/SUP], Hairong Xiong[SUP] 3 [/SUP], Deyin Guo[SUP] 5 [/SUP], Jingyou Yu[SUP] 5 [/SUP], Liangjun Chen[SUP] 6 [/SUP], Yirong Li[SUP] 6 [/SUP], Wei Hou[SUP] 7 [/SUP], Shuliang Chen[SUP] 8 [/SUP]
Affiliations
- PMID: 39251053
- DOI: 10.1016/j.cellsig.2024.111387
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.