Article Dans Une Revue Science Année : 2024

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

Hyoungjun Ham (1, 2, 3) , Huie Jing (1, 3) , Ian Lamborn (1, 4, 3) , Megan Kober (1, 3) , Alexey Koval (5) , Yamina Berchiche (6) , D. Eric Anderson (7) , Kirk Druey (3) , Judith Mandl (3) , Bertrand Isidor (8, 9) , Carlos Ferreira (10) , Alexandra Freeman (11, 3) , Sundar Ganesan (11, 3) , Meliha Karsak (12) , Peter Mustillo (13, 14) , Juliana Teo (15) , Zarazuela Zolkipli-Cunningham (16, 4) , Nicolas Chatron (17, 18) , François Lecoquierre (19) , Andrew Oler (3) , Jana Pachlopnik Schmid (20, 21) , Douglas Kuhns (22) , Xuehua Xu (3) , Fabian Hauck (23) , Waleed Al-Herz (24) , Matias Wagner (25, 26) , Paulien Terhal (27) , Mari Muurinen (28, 29, 30) , Vincent Barlogis (31, 32) , Phillip Cruz (3) , Jeffrey Danielson (3) , Helen Stewart (33) , Petra Loid (28, 29, 30) , Sebastian Rading (12) , Boris Keren (34, 35) , Rolph Pfundt (36) , Kol Zarember (3) , Katharina Vill (26, 37) , Lorraine Potocki (38, 39) , Kenneth Olivier (40) , Gaetan Lesca (41, 18) , Laurence Faivre (42, 43) , Melanie Wong (15) , Anne Puel (6, 44, 45) , Janet Chou (46) , Maud Tusseau (41, 47) , Niki Moutsopoulos (48) , Helen Matthews (3) , Cas Simons (49, 50) , Ryan Taft (51, 52) , Ariane Soldatos (53) , Etienne Masle-Farquhar (54, 49) , Stefania Pittaluga (55) , Robert Brink (56, 49) , Danielle Fink (22) , Heidi Kong (48) , Juraj Kabat (3) , Woo Sung Kim (3) , Tatjana Bierhals (12) , Kazuyuki Meguro (10) , Amy Hsu (3) , Jingwen Gu (3) , Jennifer Stoddard (48) , Benito Banos-Pinero (33) , Maria Slack (57) , Giampaolo Trivellin (58) , Benoît Mazel (59, 43) , Maarja Soomann (21) , Samuel Li (3) , Val Watts (60) , Constantine Stratakis (58) , Maria Rodriguez-Quevedo (61) , Ange-Line Bruel (42, 43) , Marita Lipsanen-Nyman (29, 30) , Paul Saultier (31, 62) , Rashmi Jain (33) , Daphne Lehalle (63) , Daniel Torres (3) , Kathleen Sullivan (16) , Sébastien Barbarot (64) , Axel Neu (12) , Yannis Duffourd (42, 49) , Morgan Similuk (3) , Kirsty Mcwalter (65) , Pierre Blanc (35) , Stéphane Bézieau (66, 9) , Tian Jin (3) , Raif Geha (46) , Jean-Laurent Casanova (6, 67, 68, 69) , Outi Makitie (28, 30, 29) , Christian Kubisch (12) , Patrick Edery (41, 70, 71) , John Christodoulou (72, 73, 50) , Ronald Germain (3) , Christopher Goodnow (49) , Thomas Sakmar (74, 6) , Daniel Billadeau (61) , Sébastien Küry (66, 9) , Vladimir Katanaev (5, 75) , Yu Zhang (3) , Michael Lenardo (3, 4) , Helen Su (3, 4)
1 LCIM - Laboratory of Clinical Immunology and Microbiology [Bethesda, MA, USA]
2 Mayo Clinic [Rochester]
3 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
4 Perelman School of Medicine
5 UNIGE - Université de Genève = University of Geneva
6 Rockefeller University [New York]
7 NIDDK - Laboratory of Biological Modeling
8 Hôtel-Dieu de Nantes
9 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
10 NHGRI - National Human Genome Research Institute
11 NIH - National Institutes of Health [Bethesda, MD, USA]
12 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
13 Nationwide Children's Hospital
14 OSU - The Ohio State University [Columbus]
15 Children's Hospital [Westmead, Australia]
16 CHOP - Children’s Hospital of Philadelphia
17 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
18 INMG-AR - Institut NeuroMyoGène - Appui à la recherche
19 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
20 UZH - Universität Zürich [Zürich] = University of Zurich
21 University Children’s Hospital Zurich
22 FNLCR - Frederick National Laboratory for Cancer Research
23 LMU - Fakultät für Physik - Ludwig-Maximilians-Universität [München/Munich]
24 Kuwait University
25 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
26 University Hospital LMU Munich
27 UMCU - University Medical Center [Utrecht]
28 Folkhälsan Research Center
29 HUS - Helsinki University Hospital [Finland]
30 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
31 TIMONE - Hôpital de la Timone [CHU - APHM]
32 CEReSS - Centre d'études et de recherche sur les services de santé et la qualité de vie
33 Oxford University Hospitals NHS Trust
34 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
35 seqOIA - Laboratoire de Biologie Médicale SeqOIA [Paris]
36 Donders Institute for Brain, Cognition and Behaviour
37 Dr von Hauner Children's Hospital [Munich, Germany]
38 BCM - Baylor College of Medicine
39 Texas Children's Hospital [Houston, USA]
40 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
41 HCL - Hospices Civils de Lyon
42 GAD - Génétique des anomalies du développement (CTM UMR 1231)
43 FHU TRANSLAD (CHU de Dijon)
44 Necker Branch - INSERM U1163 - Laboratory of Human Genetics of Infectious Diseases
45 iPSC - Plateforme IPS = Imagine Institute iPSC core facility
46 HMS - Harvard Medical School [Boston]
47 CIRI-LYACTS - Activation et transduction du signal dans les lymphocytes - Lymphocyte activation and signaling [CIRI]
48 National Institute of Health
49 Garvan Institute of medical research
50 MCRI - Murdoch Children's Research Institute
51 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
52 Illumina
53 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
54 UNSW Faculty of Medicine [Sydney]
55 NCI-NIH - National Cancer Institute [Bethesda]
56 St. Vincent’s Clinical School [Sydney, Australia]
57 URMC - University of Rochester Medical Center
58 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
59 CRMR des déficiences intellectuelles de causes rares - Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon)
60 Purdue University [West Lafayette]
61 Schulze Center for Novel Therapeutics, Division of Oncology Research [Rochester]
62 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
63 CHU Trousseau [APHP]
64 PhAN - Physiopathologie des Adaptations Nutritionnelles
65 GeneDx [Gaithersburg, MD, USA]
66 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
67 Equipe Inserm U1163 - Genetic skin diseases : from disease mechanism to therapies
68 HHMI - Howard Hughes Medical Institute [New York]
69 Hôpital Necker - Enfants Malades [AP-HP]
70 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
71 UCBL - Université Claude Bernard Lyon 1
72 University of Melbourne
73 The University of Sydney
74 Karolinska Institutet [Stockholm]
75 FEFU - Far Eastern Federal University [Vladivostok]
D. Eric Anderson
Juliana Teo
François Lecoquierre
Waleed Al-Herz
Paulien Terhal
Janet Chou
Niki Moutsopoulos
Stefania Pittaluga
Heidi Kong
Maarja Soomann
Val Watts
Daphne Lehalle
Kirsty Mcwalter
Raif Geha

Résumé

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , 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 αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 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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Dates et versions

hal-04816525 , version 1 (03-12-2024)

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Hyoungjun Ham, Huie Jing, Ian Lamborn, Megan Kober, Alexey Koval, et al.. Germline mutations in a G protein identify signaling cross-talk in T cells. Science, 2024, 385 (6715), pp.eadd8947. ⟨10.1126/science.add8947⟩. ⟨hal-04816525⟩
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