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; Stefano 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

J Allergy Clin Immunol. 2017 Aug;140(2):543-552.e5. doi: 10.1016/j.jaci.2016.10.031. Epub 2017 Jan 10.

Authors

Isabelle Melki¹, Yoann Rose², Carolina Uggenti², Lien Van Eyck³, Marie-Louise Frémond⁴, Naoki Kitabayashi², Gillian I Rice⁵, Emma M Jenkinson⁵, Anaïs Boulai², Nadia Jeremiah⁶, Marco Gattorno⁷, Stefano Volpi⁷, Olivero Sacco⁸, Suzanne W J Terheggen-Lagro⁹, Harm A W M Tiddens¹⁰, Isabelle Meyts¹¹, Marie-Anne Morren¹², Petra De Haes¹³, Carine Wouters¹⁴, Eric Legius¹⁵, Anniek Corveleyn¹⁶, Frederic Rieux-Laucat⁶, Christine Bodemer¹⁷, Isabelle Callebaut¹⁸, Mathieu P Rodero², Yanick J Crow¹⁹

Affiliations

¹ INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debré, AP-HP, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
² INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
³ INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
⁴ INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
⁵ Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.
⁶ Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Paris, France.
⁷ UO Pediatria 2 Reumatologia, G. Gaslini, Genova, Italy.
⁸ UO Pneumologia, G. Gaslini, Genova, Italy.
⁹ Department of Paediatric, Pulmonology Emma Children's Hospital AMC DD, Amsterdam, The Netherlands.
¹⁰ Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Respiratory Medicine and Allergology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
¹¹ Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
¹² Department of Dermatology, University Hospitals Leuven, Leuven, Belgium.
¹³ Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium; Department of Dermatology, University Hospitals Leuven, Leuven, Belgium.
¹⁴ Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
¹⁵ Department of Human Genetics, KU Leuven, Leuven, Belgium; Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
¹⁷ Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Dermatology Department, National Reference Center for Rare Skin Diseases MAGEC, Hôpital Necker-Enfants Malades, Paris, France.
¹⁸ CNRS UMR7590, Sorbonne Université, Université Pierre et Marie Curie-Paris6-MNHN-IRD-IUC, Paris, France.
¹⁹ INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom. Electronic address: [email protected].

PMID: 28087229
DOI: 10.1016/j.jaci.2016.10.031

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: STING-associated vasculopathy with onset in infancy; Stimulator of interferon genes (STING); TMEM173; interferon; type I interferonopathy.

Publication types

Case Reports

MeSH terms

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

Substances

Interferon Type I
Membrane Proteins
STAT1 Transcription Factor
STAT1 protein, human
STING1 protein, human