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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.

ABSTRACT: Excessive type I interferon (IFN?/?) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN?/?, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN?/? signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN?/? signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN?/? activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

SUBMITTER: Duncan CJA

PROVIDER: S-EPMC7115903 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.

Duncan Christopher J A CJA Thompson Benjamin J BJ Chen Rui R Rice Gillian I GI Gothe Florian F Young Dan F DF Lovell Simon C SC Shuttleworth Victoria G VG Brocklebank Vicky V Corner Bronte B Skelton Andrew J AJ Bondet Vincent V Coxhead Jonathan J Duffy Darragh D Fourrage Cecile C Livingston John H JH Pavaine Julija J Cheesman Edmund E Bitetti Stephania S Grainger Angela A Acres Meghan M Innes Barbara A BA Mikulasova Aneta A Sun Ruyue R Hussain Rafiqul R Wright Ronnie R Wynn Robert R Zarhrate Mohammed M Zeef Leo A H LAH Wood Katrina K Hughes Stephen M SM Harris Claire L CL Engelhardt Karin R KR Crow Yanick J YJ Randall Richard E RE Kavanagh David D Hambleton Sophie S Briggs Tracy A TA

Science immunology 20191201 42

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygo ...[more]

PMID: 31836668

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.

Publications

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in <i>STAT2</i>.

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