tetano
Editor, Senior Moderator
J Biol Chem. 2020 Apr 29. pii: jbc.RA120.013752. doi: 10.1074/jbc.RA120.013752. [Epub ahead of print]
The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development.
Kesavardhana S[SUP]1[/SUP], Malireddi RKS[SUP]2[/SUP], Burton AR[SUP]1[/SUP], Porter SN[SUP]1[/SUP], Vogel P[SUP]1[/SUP], Pruett-Miller SM[SUP]1[/SUP], Kanneganti TD[SUP]1[/SUP].
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Abstract
Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates both host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1[SUP]ΔZα2/ΔZα2[/SUP] mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and underlies the perinatal lethality in mice in which the RHIM domain of RIPK1 had been mutated (Ripk1[SUP]mRHIM/mRHIM[/SUP]). Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1[SUP]mRHIM/mRHIM[/SUP] mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
KEYWORDS:
RNA virus; infection; influenza; influenza virus; microbiology; negative-strand RNA virus
PMID:32350114DOI:10.1074/jbc.RA120.013752
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The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development.
Kesavardhana S[SUP]1[/SUP], Malireddi RKS[SUP]2[/SUP], Burton AR[SUP]1[/SUP], Porter SN[SUP]1[/SUP], Vogel P[SUP]1[/SUP], Pruett-Miller SM[SUP]1[/SUP], Kanneganti TD[SUP]1[/SUP].
Author information
Abstract
Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates both host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1[SUP]ΔZα2/ΔZα2[/SUP] mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and underlies the perinatal lethality in mice in which the RHIM domain of RIPK1 had been mutated (Ripk1[SUP]mRHIM/mRHIM[/SUP]). Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1[SUP]mRHIM/mRHIM[/SUP] mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
KEYWORDS:
RNA virus; infection; influenza; influenza virus; microbiology; negative-strand RNA virus
PMID:32350114DOI:10.1074/jbc.RA120.013752
Free full text