The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses double-stranded DNA in the cytoplasm, triggering the secretion of type I and III interferons and proinflammatory cytokines. However, cGAS-STING pathway activation by STING agonists also induces regulated cell death (RCD) in human monocytes, which is inherently linked to cytokine production. We identified that STING agonist-induced monocyte RCD integrates apoptotic (active caspase-9, -8 and -3/7) and pyroptotic mechanisms (active caspase-1, cleaved gasdermin-D and secreted mature interleukin-1β and -18), whereas necroptosis is inhibited through caspase-8-mediated cleavage of receptor-interacting protein kinase 1 (RIPK1). Additionally, this RCD is accompanied by mitochondrial dysfunction, which precedes caspase activation, suggesting that mitochondrial disruption may act as both the driving mechanism and a direct outcome of cGAS-STING pathway activation via the STING-IRF3-BAX pathway. Overall, this study identifies a novel RCD process that may be described as 'pyroptotic apoptosis', providing new insights into the outcomes of cGAS-STING signalling in human monocytes.

Department of Genetics and Microbiology Faculty of Science Charles University BIOCEV Vestec Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Pancreatic Islet Research Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

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