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

Christopher J.A. Duncan; Benjamin J. Thompson; Rui Chen; Gillian I. Rice; Florian Gothe; Dan F. Young; Simon C. Lovell; Victoria G. Shuttleworth; Vicky Brocklebank; Bronte Corner; Andrew J. Skelton; Vincent Bondet; Jonathan Coxhead; Darragh Duffy; Cecile Fourrage; John H. Livingston; Julija Pavaine; Edmund Cheesman; Stephania Bitetti; Angela Grainger; Meghan Acres; Barbara A. Innes; Aneta Mikulasova; Ruyue Sun; Rafiqul Hussain; Ronnie Wright; Robert Wynn; Mohammed Zarhrate; Leo A.H. Zeef; Katrina Wood; Stephen M. Hughes; Claire L. Harris; Karin R. Engelhardt; Yanick J. Crow; Richard E. Randall; David Kavanagh; Sophie Hambleton; Tracy A. Briggs

doi:10.1126/sciimmunol.aav7501

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

Christopher J.A. Duncan^*, Benjamin J. Thompson, Rui Chen, Gillian I. Rice, Florian Gothe, Dan F. Young, Simon C. Lovell, Victoria G. Shuttleworth, Vicky Brocklebank, Bronte Corner, Andrew J. Skelton, Vincent Bondet, Jonathan Coxhead, Darragh Duffy, Cecile Fourrage, John H. Livingston, Julija Pavaine, Edmund Cheesman, Stephania Bitetti, Angela GraingerMeghan Acres, Barbara A. Innes, Aneta Mikulasova, Ruyue Sun, Rafiqul Hussain, Ronnie Wright, Robert Wynn, Mohammed Zarhrate, Leo A.H. Zeef, Katrina Wood, Stephen M. Hughes, Claire L. Harris, Karin R. Engelhardt, Yanick J. Crow, Richard E. Randall, David Kavanagh, Sophie Hambleton^*, Tracy A. Briggs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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 STAT2^R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, 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 STAT2^R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Original language	English
Article number	eaav7501
Journal	Science Immunology
Volume	4
Issue number	42
DOIs	https://doi.org/10.1126/sciimmunol.aav7501
Publication status	Published - 13 Dec 2019

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Duncan, C. J. A., Thompson, B. J., Chen, R., Rice, G. I., Gothe, F., Young, D. F., Lovell, S. C., Shuttleworth, V. G., Brocklebank, V., Corner, B., Skelton, A. J., Bondet, V., Coxhead, J., Duffy, D., Fourrage, C., Livingston, J. H., Pavaine, J., Cheesman, E., Bitetti, S., ... Briggs, T. A. (2019). Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Science Immunology, 4(42), Article eaav7501. https://doi.org/10.1126/sciimmunol.aav7501

@article{0b7bbda0aaf246a0a2bf5d45a2a0ec46,

title = "Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2",

abstract = "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 heterozygosity) were hypersensitive to IFNα/β, 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 IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.",

author = "Duncan, \{Christopher J.A.\} and Thompson, \{Benjamin J.\} and Rui Chen and Rice, \{Gillian I.\} and Florian Gothe and Young, \{Dan F.\} and Lovell, \{Simon C.\} and Shuttleworth, \{Victoria G.\} and Vicky Brocklebank and Bronte Corner and Skelton, \{Andrew J.\} and Vincent Bondet and Jonathan Coxhead and Darragh Duffy and Cecile Fourrage and Livingston, \{John H.\} and Julija Pavaine and Edmund Cheesman and Stephania Bitetti and Angela Grainger and Meghan Acres and Innes, \{Barbara A.\} and Aneta Mikulasova and Ruyue Sun and Rafiqul Hussain and Ronnie Wright and Robert Wynn and Mohammed Zarhrate and Zeef, \{Leo A.H.\} and Katrina Wood and Hughes, \{Stephen M.\} and Harris, \{Claire L.\} and Engelhardt, \{Karin R.\} and Crow, \{Yanick J.\} and Randall, \{Richard E.\} and David Kavanagh and Sophie Hambleton and Briggs, \{Tracy A.\}",

year = "2019",

month = dec,

day = "13",

doi = "10.1126/sciimmunol.aav7501",

language = "English",

volume = "4",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "42",

}

Duncan, CJA, Thompson, BJ, Chen, R, Rice, GI, Gothe, F, Young, DF, Lovell, SC, Shuttleworth, VG, Brocklebank, V, Corner, B, Skelton, AJ, Bondet, V, Coxhead, J, Duffy, D, Fourrage, C, Livingston, JH, Pavaine, J, Cheesman, E, Bitetti, S, Grainger, A, Acres, M, Innes, BA, Mikulasova, A, Sun, R, Hussain, R, Wright, R, Wynn, R, Zarhrate, M, Zeef, LAH, Wood, K, Hughes, SM, Harris, CL, Engelhardt, KR, Crow, YJ, Randall, RE, Kavanagh, D, Hambleton, S & Briggs, TA 2019, 'Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2', Science Immunology, vol. 4, no. 42, eaav7501. https://doi.org/10.1126/sciimmunol.aav7501

TY - JOUR

T1 - Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

AU - Duncan, Christopher J.A.

AU - Thompson, Benjamin J.

AU - Chen, Rui

AU - Rice, Gillian I.

AU - Gothe, Florian

AU - Young, Dan F.

AU - Lovell, Simon C.

AU - Shuttleworth, Victoria G.

AU - Brocklebank, Vicky

AU - Corner, Bronte

AU - Skelton, Andrew J.

AU - Bondet, Vincent

AU - Coxhead, Jonathan

AU - Duffy, Darragh

AU - Fourrage, Cecile

AU - Livingston, John H.

AU - Pavaine, Julija

AU - Cheesman, Edmund

AU - Bitetti, Stephania

AU - Grainger, Angela

AU - Acres, Meghan

AU - Innes, Barbara A.

AU - Mikulasova, Aneta

AU - Sun, Ruyue

AU - Hussain, Rafiqul

AU - Wright, Ronnie

AU - Wynn, Robert

AU - Zarhrate, Mohammed

AU - Zeef, Leo A.H.

AU - Wood, Katrina

AU - Hughes, Stephen M.

AU - Harris, Claire L.

AU - Engelhardt, Karin R.

AU - Crow, Yanick J.

AU - Randall, Richard E.

AU - Kavanagh, David

AU - Hambleton, Sophie

AU - Briggs, Tracy A.

PY - 2019/12/13

Y1 - 2019/12/13

N2 - 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 heterozygosity) were hypersensitive to IFNα/β, 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 IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

AB - 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 heterozygosity) were hypersensitive to IFNα/β, 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 IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

UR - https://www.scopus.com/pages/publications/85076454576

U2 - 10.1126/sciimmunol.aav7501

DO - 10.1126/sciimmunol.aav7501

M3 - Article

C2 - 31836668

SN - 2470-9468

VL - 4

JO - Science Immunology

JF - Science Immunology

IS - 42

M1 - eaav7501

ER -

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

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