{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhou JY"],"funding":["NIAID NIH HHS","HHS | NIH","NIAMS NIH HHS","NIGMS NIH HHS"],"pagination":["e2213777120"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9945980"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["120(5)"],"pubmed_abstract":["The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 (<i>AIM2</i>) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT)."],"pmcid":["PMC9945980"],"funding_grant_id":["AI132152","GM107000","AR075043","T32 AI132152","T32 GM107000","P30 AR075043"],"pubmed_authors":["Zhou JY","Harris JE","Gudjonsson JE","Fitzgerald KA","Okamura K","Sarkar MK"],"additional_accession":[]},"is_claimable":false,"name":"Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT).","description":"The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 (<i>AIM2</i>) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2025-04-04T20:33:27.711Z","creation":"2025-04-04T20:33:27.711Z"},"accession":"S-EPMC9945980","cross_references":{"pubmed":["36693106"],"doi":["10.1073/pnas.2213777120"]}}