tetano
Editor, Senior Moderator
Cell Commun Signal
. 2024 Jul 23;22(1):372.
doi: 10.1186/s12964-024-01727-2. Influenza virus infection activates TAK1 to suppress RIPK3-independent apoptosis and RIPK1-dependent necroptosis
Yuling Sun[SUP] 1 [/SUP], Lei Ji[SUP] 1 [/SUP], Wei Liu[SUP] 1 [/SUP], Jing Sun[SUP] 1 [/SUP], Penggang Liu[SUP] 1 [/SUP], Xiaoquan Wang[SUP] 2 3 [/SUP], Xiufan Liu[SUP] 2 3 [/SUP], Xiulong Xu[SUP] 4 5 [/SUP]
Affiliations
Many DNA viruses develop various strategies to inhibit cell death to facilitate their replication. However, whether influenza A virus (IAV), a fast-replicating RNA virus, attenuates cell death remains unknown. Here, we report that IAV infection induces TAK1 phosphorylation in a murine alveolar epithelial cell line (LET1) and a murine fibroblastoma cell line (L929). The TAK1-specific inhibitor 5Z-7-Oxzeneonal (5Z) and TAK1 knockout significantly enhance IAV-induced apoptosis, as evidenced by increased PARP, caspase-8, and caspase-3 cleavage. TAK1 inhibition also increases necroptosis as evidenced by increased RIPK1[SUP]S166[/SUP], RIPK3[SUP]T231/S232[/SUP], and MLKL[SUP]S345[/SUP] phosphorylation. Mechanistically, TAK1 activates IKK, which phosphorylates RIPK1[SUP]S25[/SUP] and inhibits its activation. TAK1 also activates p38 and its downstream kinase MK2, which phosphorylates RIPK1[SUP]S321[/SUP] but does not affect RIPK1 activation. Further investigation revealed that the RIPK1 inhibitor Nec-1 and RIPK1 knockout abrogate IAV-induced apoptosis and necroptosis; re-expression of wild-type but not kinase-dead (KD)-RIPK1 restores IAV-induced cell death. ZBP1 knockout abrogates IAV-induced cell death, whereas RIPK3 knockout inhibits IAV-induced necroptosis but not apoptosis. 5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.
Keywords: Apoptosis; Influenza A virus; Necroptosis; RIPK1; TAK1.
. 2024 Jul 23;22(1):372.
doi: 10.1186/s12964-024-01727-2. Influenza virus infection activates TAK1 to suppress RIPK3-independent apoptosis and RIPK1-dependent necroptosis
Yuling Sun[SUP] 1 [/SUP], Lei Ji[SUP] 1 [/SUP], Wei Liu[SUP] 1 [/SUP], Jing Sun[SUP] 1 [/SUP], Penggang Liu[SUP] 1 [/SUP], Xiaoquan Wang[SUP] 2 3 [/SUP], Xiufan Liu[SUP] 2 3 [/SUP], Xiulong Xu[SUP] 4 5 [/SUP]
Affiliations
- PMID: 39044278
- DOI: 10.1186/s12964-024-01727-2
Many DNA viruses develop various strategies to inhibit cell death to facilitate their replication. However, whether influenza A virus (IAV), a fast-replicating RNA virus, attenuates cell death remains unknown. Here, we report that IAV infection induces TAK1 phosphorylation in a murine alveolar epithelial cell line (LET1) and a murine fibroblastoma cell line (L929). The TAK1-specific inhibitor 5Z-7-Oxzeneonal (5Z) and TAK1 knockout significantly enhance IAV-induced apoptosis, as evidenced by increased PARP, caspase-8, and caspase-3 cleavage. TAK1 inhibition also increases necroptosis as evidenced by increased RIPK1[SUP]S166[/SUP], RIPK3[SUP]T231/S232[/SUP], and MLKL[SUP]S345[/SUP] phosphorylation. Mechanistically, TAK1 activates IKK, which phosphorylates RIPK1[SUP]S25[/SUP] and inhibits its activation. TAK1 also activates p38 and its downstream kinase MK2, which phosphorylates RIPK1[SUP]S321[/SUP] but does not affect RIPK1 activation. Further investigation revealed that the RIPK1 inhibitor Nec-1 and RIPK1 knockout abrogate IAV-induced apoptosis and necroptosis; re-expression of wild-type but not kinase-dead (KD)-RIPK1 restores IAV-induced cell death. ZBP1 knockout abrogates IAV-induced cell death, whereas RIPK3 knockout inhibits IAV-induced necroptosis but not apoptosis. 5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.
Keywords: Apoptosis; Influenza A virus; Necroptosis; RIPK1; TAK1.