Germline mutations in a G protein identify signaling cross-talk in T cells

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in <i>GNAI2</i>, which encodes G<sub>αi2</sub>, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G<sub>αi2</sub> mutations had clinical presentations that included impaired immunity. Mutant G<sub>αi2</sub> impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G<sub>αi2</sub> influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

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Publication Details

Journal
Science
Published
2024-09-19
DOI
https://doi.org/10.1126/science.add8947
Citations
19
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
4.57

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Germline mutations in a G protein identify signaling cross-talk in T cells

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Science
Immunodeficiency and Autoimmune Disorders
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article

Germline mutations in a G protein identify signaling cross-talk in T cells

Stefania Pittaluga, Ian T. Lamborn, Kirk M. Druey, Kathleen E. Sullivan, Pauline Terhal, Boris Keren, Ryan J. Taft, Amy P. Hsu, Judith N. Mandl, Cas Simons, Phillip Cruz, Tatjana Bierhals, Christian Kubisch, Peter Mustillo, Samuel T. Li, Waleed Al–Herz, Helen Stewart, Helen C. Su, Kol A. Zarember, Rolph Pfundt, Andrew J. Oler, Jeffrey J. Danielson, Douglas B. Kuhns, François Lecoquierre, Fabian Hauck, Maarja Soomann, Laurence Olivier Faivre, Heidi H. Kong, Daphné Lehalle, Mari Muurinen, Yamina A. Berchiche, Huie Jing, Niki M. Moutsopoulos, Constantine A. Stratakis, Ariane Soldatos, Meliha Karsak, Lorraine Potocki, Janet Chou, Sébastien Küry, Marita Lipsanen‐Nyman, Kazuyuki Meguro, Alexey Koval, S. Barbarot, Rashmi Jain, Paul Saultier, John Christodoulou, Danielle Fink, Jean‐Laurent Casanova, Zarazuela Zolkipli‐Cunningham, Sundar Ganesan, Vincent Barlogis, Gaëtan Lesca, Carlos R. Ferreira, Axel Neu, Matias Wagner, Ange‐Line Bruel, Bertrand Isidor, Robert Brink, M. Kober, Anne Puel, Katharina Vill, Alexandra F. Freeman, Xuehua Xu, Outi Mäkitie, Val J. Watts, Giampaolo Trivellin, Pierre Blanc, Sebastian Rading, Christopher C. Goodnow, Michael J. Lenardo, Maria A. Slack, Petra Loid, Benoît Mazel, Thomas P. Sakmar, Hyoungjun Ham, David E. Anderson, Daniel D. Billadeau, Morgan N. Similuk, Juraj Kabát, Stéphane Bezieau, Vladimir L. Katanaev, Patrick Edery, Jana Pachlopnik Schmid, Jennifer Stoddard, Ronald N. Germain, Kirsty McWalter, Etienne Masle‐Farquhar, Nicolas Chatron, Yu Zhang, Woo Sung Kim, Melanie Wong, Jingwen Gu, Juliana Teo, Daniel Torres, Maria F. Rodriguez-Quevedo, Benito Banos-Pinero, Yannis Duffourd, Helen Matthews, Tian Jin, Maud Tusseau, Raif S. Geha, Kenneth N. Olivier
article en
19 citations

Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in <i>GNAI2</i>, which encodes G<sub>αi2</sub>, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G<sub>αi2</sub> mutations had clinical presentations that included impaired immunity. Mutant G<sub>αi2</sub> impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G<sub>αi2</sub> influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

ScienceVol. 385(6715)
Université Claude Bernard Lyon 1 (FR), University of Geneva (CH), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), The University of Sydney (AU), National Institutes of Health (US), Nationwide Children's Hospital (US), Mayo Clinic (US), Children's Hospital of Philadelphia (US), University of Helsinki (FI), Howard Hughes Medical Institute (US), Harvard University (US), Garvan Institute of Medical Research (AU), Radboud University Nijmegen (NL), Inserm (FR), Universität Hamburg (DE), The University of Queensland (AU), The University of Melbourne (AU), Université de Bourgogne (FR), Illumina (United States) (US), Baylor College of Medicine (US), University of Zurich (CH), Université Paris Cité (FR), Far Eastern Federal University (RU), Aix-Marseille Université (FR), Purdue University West Lafayette (US), Helsinki University Hospital (FI), Nuffield Orthopaedic Centre (GB), Children's Hospital at Westmead (AU), Radboud University Medical Center (NL), Karolinska Institutet (SE), Helmholtz Zentrum München (DE), University Medical Center Utrecht (NL), UNSW Sydney (AU), Kuwait University (KW), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Assistance Publique Hôpitaux de Marseille (FR), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), National Institute of Dental and Craniofacial Research (US), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), National Human Genome Research Institute (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Centre de Recherche en Neurosciences de Lyon (FR), Assistance Publique – Hôpitaux de Paris (FR), Center for Children (US), Hospices Civils de Lyon (FR), Futures Group (United States) (US), Novel (United States) (US), Normandie Université (FR), National Heart, Lung, and Blood Institute (US), University Medical Center Hamburg-Eppendorf (DE), National Institute of Neurological Disorders and Stroke (US), CHU Dijon Bourgogne (FR), ID Genomics (United States) (US), Institute of Human Genetics (PL), München Klinik (DE), Golisano Children's Hospital (US), St Vincent's Clinic (AU), Institut NeuroMyoGène (FR), Immungenetics (Germany) (DE), University Children's Hospital Zurich (CH), Al-Sabah Hospital (KW), Frederick National Laboratory for Cancer Research (US), National Institute of Allergy and Infectious Diseases (US), Office of the Director (US), Institut du Thorax (FR), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), Immune Regulation (United Kingdom) (GB), Oxford University Hospitals NHS Trust (GB), Texas Children's Hospital (US), Center for Cancer Research (US), Murdoch Children's Research Institute (AU), Sequoia (United States) (US), National Institutes of Health Clinical Center (US), Génétique Médicale & Génomique Fonctionelle (FR), Centre International de Recherche en Infectiologie (FR), PhysioPathologie des Adaptations Nutritionnelles (FR), Hôpital de la Timone (FR), Institut des Maladies Génétiques Imagine (FR), Folkhälsans Forskningscentrum (FI), The Ohio State University (US), Université de Rouen Normandie (FR), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Rockefeller University (US), Nantes Université (FR)
National Science Foundation, U.S. Department of Health and Human Services, Mayo Clinic, St. Giles Foundation, Purdue University, University of Pennsylvania, Care-for-Rare Foundation, Children’s Hospital of Wisconsin Research Institute, Children's Hospital Foundation, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Georgia Clinical and Translational Science Alliance, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Else Kröner-Fresenius-Stiftung, Korea Research Institute of Bioscience and Biotechnology, State Government of Victoria, Lastentautien Tutkimussäätiö, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Sigrid Juséliuksen Säätiö, National Institutes of Health, U.S. Public Health Service, University of California, San Francisco, Medical Research Council, National Health and Medical Research Council, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, National Center for Advancing Translational Sciences
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Immunodeficiency and Autoimmune Disorders
4.57
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