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The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells.

Competing Interests: Declaration of interests S.J.B. is a co-founder, VP Science Strategy, and shareholder at Artios Pharma Ltd. C.T.H. acknowledges grant support from Hoffman La Roche, has received speaker fees from AstraZeneca and Eli Lilly, and has a paid advisory role for GenesisCare UK.

Titel:	Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING.
Autor/in / Beteiligte Person:	Takaki, T ; Millar, R ; Hiley, CT ; Boulton, SJ
Zeitschrift:	Molecular cell, Jg. 84 (2024-06-06), Heft 11, S. 2203
Veröffentlichung:	Cambridge Ma : Cell Press ; <i>Original Publication</i>: Cambridge, Mass. : Cell Press, c1997-, 2024
Medientyp:	academicJournal
ISSN:	1097-4164 (electronic)
DOI:	10.1016/j.molcel.2024.04.017
Schlagwort:	Humans Phosphorylation DNA Replication radiation effects Protein Serine-Threonine Kinases metabolism Protein Serine-Threonine Kinases genetics Interferon Regulatory Factor-3 metabolism Interferon Regulatory Factor-3 genetics Immunity, Innate radiation effects DNA Damage HEK293 Cells Animals Radiation, Ionizing HeLa Cells Nucleotidyltransferases metabolism Nucleotidyltransferases genetics Membrane Proteins metabolism Membrane Proteins genetics Signal Transduction Micronuclei, Chromosome-Defective radiation effects Nucleotides, Cyclic metabolism Chromosome Segregation
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Mol Cell] 2024 Jun 06; Vol. 84 (11), pp. 2203-2213.e5. <i>Date of Electronic Publication: </i>2024 May 14. MeSH Terms: Nucleotidyltransferases* / metabolism ; Nucleotidyltransferases* / genetics ; Membrane Proteins* / metabolism ; Membrane Proteins* / genetics ; Signal Transduction* ; Micronuclei, Chromosome-Defective* / radiation effects ; Nucleotides, Cyclic* / metabolism ; Chromosome Segregation* ; Humans ; Phosphorylation ; DNA Replication / radiation effects ; Protein Serine-Threonine Kinases / metabolism ; Protein Serine-Threonine Kinases / genetics ; Interferon Regulatory Factor-3 / metabolism ; Interferon Regulatory Factor-3 / genetics ; Immunity, Innate / radiation effects ; DNA Damage ; HEK293 Cells ; Animals ; Radiation, Ionizing ; HeLa Cells Contributed Indexing: Keywords: DNA damage; IRF3; STING; cGAS; chromosome missegregation; innate immune response; micronuclei; radiation; replication stress Substance Nomenclature: EC 2.7.7.- (Nucleotidyltransferases) ; EC 2.7.7.- (cGAS protein, human) ; 0 (Membrane Proteins) ; 0 (STING1 protein, human) ; 0 (Nucleotides, Cyclic) ; 0 (cyclic guanosine monophosphate-adenosine monophosphate) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) ; 0 (Interferon Regulatory Factor-3) ; 0 (IRF3 protein, human) ; EC 2.7.11.1 (TBK1 protein, human) Entry Date(s): Date Created: 20240515 Date Completed: 20240607 Latest Revision: 20240608 Update Code: 20240609

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Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING.