Cytosolic RNA:DNA hybrids activate the <scp>cGAS</scp>–STING axis

Mankan, Arun K.; Schmidt, Tobias; Chauhan, Dhruv; Goldeck, Marion; Höning, Klara; Gaidt, Moritz M.; Kubarenko, Andriy V.; Andreeva, Liudmila; Hopfner, Karl‐Peter; Hornung, Veit

doi:10.15252/embj.201488726

Cited by 262 publications

(221 citation statements)

References 39 publications

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“…Finally, the fact that both dsDNA (Sun et al , 2013; Gao et al , 2013) and RNA:DNA hybrids (Mankan et al , 2014) can bind and activate the cytoplasmic nucleic acid sensor cGAS prompted us to consider the origin of the cGAS ligand present in RNase H2‐deficient cells. Abrogated RNase H2 function could give rise to cytosolic accumulation of RNA:DNA heteroduplexes as a consequence of reduced RNA:DNA degradation of structures such as R‐loops or active retroelements/endogenous retroviruses (Chon et al , 2013; Rigby et al , 2014; Moelling & Broecker, 2015).…”

Section: Resultsmentioning

confidence: 99%

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

et al. 2016

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Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA:DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway. Here, we establish Rnaseh2b A174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene (ISG) transcript upregulation that recapitulates the ISG signature seen in AGS patients. The inflammatory response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage. This suggests that cGAS/STING is a key nucleic acid‐sensing pathway relevant to AGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.

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Section: Resultsmentioning

confidence: 99%

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

et al. 2016

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“…In TykNu, knockdown of TLR3 and MAVS significantly blunted Aza induction of these gene responses ( Figure S4b,c). Importantly, knockdown of STING, the cytosolic DNA sensor (Mankan et al, 2014) did not blunt Aza induced interferon signaling (Figure 4c,d). A previous report had implicated STING in viral cytosolic sensing in B cells, but this was dependent upon viral reverse transcriptase activity, likely to be low in our cells (Mankan et al, 2014).…”

Section: Dnmtis Trigger Viral Defense Through Induction Of Dsrnamentioning

confidence: 92%

“…Importantly, knockdown of STING, the cytosolic DNA sensor (Mankan et al, 2014) did not blunt Aza induced interferon signaling (Figure 4c,d). A previous report had implicated STING in viral cytosolic sensing in B cells, but this was dependent upon viral reverse transcriptase activity, likely to be low in our cells (Mankan et al, 2014). We thus conclude that MAVS and TLR3 are centrally involved in Aza triggering cytosolic sensors to induce an interferon response.…”

Section: Dnmtis Trigger Viral Defense Through Induction Of Dsrnamentioning

confidence: 92%

“…The above data suggests Aza might activate endogenous retroviral sequences (ERVs) that constitute more than 8% of the human genome, can activate cytosolic RNA sensors, and are silenced in normal somatic cells by promoter DNA methylation (Bannert and Kurth, 2004) (Tristem, 2000) (Hurst and Magiorkinis, 2014) (Mankan et al, 2014). Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing.…”

Section: Aza-induced Human Endogenous Retrovirus (Erv) Transcripts Camentioning

confidence: 99%

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Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli¹,

Strissel²,

Desrichard³

et al. 2017

Cell

102

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SummaryWe show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Correspondence should be addressed to Reiner.Strick@uk-erlangen.de and sbaylin@jhmi.edu.. 7 Co-first authors. 8 Co-senior authors.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions KBC, PLS, AD, TM, JW, TAC, SBB, and RS designed experiments, performed data analyses, and wrote the manuscript. KBC, PLS, CH, AD, AH, BA, and SB performed experiments. NSR provided ERV-3 env cDNA plasmid and DS provided ovarian cancer cell lines. HL, AS, VM, DMP, LMC, MWB, and CAZ assisted with data analyses. TM, TAC, SBB, and RS contributed equally to this work and are co-senior authors. HHS Public Access

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“…Among these is cGAS, an innate DNA sensor, which, on recognition of dsDNA or RNA:DNA hybrids in the cytoplasm, generates 2′3′ cGMP-AMP (2′3′cGAMP) (36)(37)(38)(39)(40)(41). cGAMP then binds to stimulator of IFN genes (STING, also known as TMEM173, MITA, ERIS, or MPYS), which recruits and activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to induce the expression of type I IFNs, which in turn induce expression of IFN-stimulated genes (ISGs).…”

Section: Significancementioning

confidence: 99%

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Zhang

Chan

Samarina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

135

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The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGASmediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.KSHV | cytoplasmic LANA | cyclic GMP-AMP synthase

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Cytosolic RNA:DNA hybrids activate the cGAS–STING axis

Cited by 262 publications

References 39 publications

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

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