Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

Isabelle Melki; Yoann Rose; Carolina Uggenti; Lien Van Eyck; Marie-louise Frémond; Naoki Kitabayashi; Gillian I. Rice; Emma M. Jenkinson; Anaïs Boulai; Nadia Jeremiah; Marco Gattorno; Sefano Volpi; Olivero Sacco; Suzanne W.j. Terheggen-lagro; Harm A.w.m. Tiddens; Isabelle Meyts; Marie-anne Morren; Petra De Haes; Carine Wouters; Eric Legius; Anniek Corveleyn; Frederic Rieux-laucat; Christine Bodemer; Isabelle Callebaut; Mathieu P. Rodero; Yanick J. Crow

doi:10.1016/j.jaci.2016.10.031

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

Isabelle Melki, Yoann Rose, Carolina Uggenti, Lien Van Eyck, Marie-louise Frémond, Naoki Kitabayashi, Gillian I. Rice, Emma M. Jenkinson, Anaïs Boulai, Nadia Jeremiah, Marco Gattorno, Sefano Volpi, Olivero Sacco, Suzanne W.j. Terheggen-lagro, Harm A.w.m. Tiddens, Isabelle Meyts, Marie-anne Morren, Petra De Haes, Carine Wouters, Eric LegiusAnniek Corveleyn, Frederic Rieux-laucat, Christine Bodemer, Isabelle Callebaut, Mathieu P. Rodero, Yanick J. Crow

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

Abstract / Description of output

BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).

OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.

METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.

RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.

CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.

Original language	English
Pages (from-to)	543-552.e5
Journal	Journal of Allergy and Clinical Immunology
Volume	140
Issue number	2
Early online date	10 Jan 2017
DOIs	https://doi.org/10.1016/j.jaci.2016.10.031
Publication status	Published - 1 Aug 2017

Keywords / Materials (for Non-textual outputs)

Adolescent
Adult
Amino Acid Substitution
Child
Female
HEK293 Cells
Humans
Inflammation/genetics
Interferon Type I/genetics
Male
Membrane Proteins/genetics
Mutation
STAT1 Transcription Factor/metabolism
Signal Transduction

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10.1016/j.jaci.2016.10.031

http://linkinghub.elsevier.com/retrieve/pii/S0091674916314385

Yanick Crow
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genomic Medicine
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
Person: Academic: Research Active

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Melki, I., Rose, Y., Uggenti, C., Van Eyck, L., Frémond, M., Kitabayashi, N., Rice, G. I., Jenkinson, E. M., Boulai, A., Jeremiah, N., Gattorno, M., Volpi, S., Sacco, O., Terheggen-lagro, S. W. J., Tiddens, H. A. W. M., Meyts, I., Morren, M., De Haes, P., Wouters, C., ... Crow, Y. J. (2017). Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. Journal of Allergy and Clinical Immunology, 140(2), 543-552.e5. https://doi.org/10.1016/j.jaci.2016.10.031

@article{9eb8fcbec2e44451aa05c6fd26bbb5da,

title = "Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling",

abstract = "BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.",

keywords = "Adolescent, Adult, Amino Acid Substitution, Child, Female, HEK293 Cells, Humans, Inflammation/genetics, Interferon Type I/genetics, Male, Membrane Proteins/genetics, Mutation, STAT1 Transcription Factor/metabolism, Signal Transduction",

author = "Isabelle Melki and Yoann Rose and Carolina Uggenti and {Van Eyck}, Lien and Marie-louise Fr{\'e}mond and Naoki Kitabayashi and Rice, {Gillian I.} and Jenkinson, {Emma M.} and Ana{\"i}s Boulai and Nadia Jeremiah and Marco Gattorno and Sefano Volpi and Olivero Sacco and Terheggen-lagro, {Suzanne W.j.} and Tiddens, {Harm A.w.m.} and Isabelle Meyts and Marie-anne Morren and {De Haes}, Petra and Carine Wouters and Eric Legius and Anniek Corveleyn and Frederic Rieux-laucat and Christine Bodemer and Isabelle Callebaut and Rodero, {Mathieu P.} and Crow, {Yanick J.}",

year = "2017",

month = aug,

day = "1",

doi = "10.1016/j.jaci.2016.10.031",

language = "English",

volume = "140",

pages = "543--552.e5",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

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number = "2",

}

Melki, I, Rose, Y, Uggenti, C, Van Eyck, L, Frémond, M, Kitabayashi, N, Rice, GI, Jenkinson, EM, Boulai, A, Jeremiah, N, Gattorno, M, Volpi, S, Sacco, O, Terheggen-lagro, SWJ, Tiddens, HAWM, Meyts, I, Morren, M, De Haes, P, Wouters, C, Legius, E, Corveleyn, A, Rieux-laucat, F, Bodemer, C, Callebaut, I, Rodero, MP & Crow, YJ 2017, 'Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling', Journal of Allergy and Clinical Immunology, vol. 140, no. 2, pp. 543-552.e5. https://doi.org/10.1016/j.jaci.2016.10.031

TY - JOUR

T1 - Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

AU - Melki, Isabelle

AU - Rose, Yoann

AU - Uggenti, Carolina

AU - Van Eyck, Lien

AU - Frémond, Marie-louise

AU - Kitabayashi, Naoki

AU - Rice, Gillian I.

AU - Jenkinson, Emma M.

AU - Boulai, Anaïs

AU - Jeremiah, Nadia

AU - Gattorno, Marco

AU - Volpi, Sefano

AU - Sacco, Olivero

AU - Terheggen-lagro, Suzanne W.j.

AU - Tiddens, Harm A.w.m.

AU - Meyts, Isabelle

AU - Morren, Marie-anne

AU - De Haes, Petra

AU - Wouters, Carine

AU - Legius, Eric

AU - Corveleyn, Anniek

AU - Rieux-laucat, Frederic

AU - Bodemer, Christine

AU - Callebaut, Isabelle

AU - Rodero, Mathieu P.

AU - Crow, Yanick J.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.

AB - BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.

KW - Adolescent

KW - Adult

KW - Amino Acid Substitution

KW - Child

KW - Female

KW - HEK293 Cells

KW - Humans

KW - Inflammation/genetics

KW - Interferon Type I/genetics

KW - Male

KW - Membrane Proteins/genetics

KW - Mutation

KW - STAT1 Transcription Factor/metabolism

KW - Signal Transduction

U2 - 10.1016/j.jaci.2016.10.031

DO - 10.1016/j.jaci.2016.10.031

M3 - Article

C2 - 28087229

SN - 0091-6749

VL - 140

SP - 543-552.e5

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 2

ER -

Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

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Keywords / Materials (for Non-textual outputs)

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Yanick Crow

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