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

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

doi:10.1126/science.add8947

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

Hyoungjun Ham
, Huie Jing
, Ian T. Lamborn
, Megan M. Kober
, Alexey Koval
, Yamina A. Berchiche
, D. Eric Anderson
, Kirk M. Druey
, Judith N. Mandl
, Bertrand Isidor
, Carlos R. Ferreira
, Alexandra F. Freeman
, Sundar Ganesan
, Meliha Karsak
, Peter J. Mustillo
, Juliana Teo
, Zarazuela Zolkipli-Cunningham
, Nicolas Chatron
, François Lecoquierre
, Andrew J. Oler

Jana Pachlopnik Schmid, Douglas B. Kuhns, Xuehua Xu, Fabian Hauck, Waleed Al-Herz, Matias Wagner, Paulien A. Terhal, Mari Muurinen, Vincent Barlogis, Phillip Cruz, Jeffrey Danielson, Helen Stewart, Petra Loid, Sebastian Rading, Boris Keren, Rolph Pfundt, Kol A. Zarember, Katharina Vill, Lorraine Potocki, Kenneth N. Olivier, Gaetan Lesca, Laurence Faivre, Melanie Wong, Anne Puel, Janet Chou, Maud Tusseau, Niki M. Moutsopoulos, Helen F. Matthews, Cas Simons, Ryan J. Taft, Ariane Soldatos, Etienne Masle-Farquhar, Stefania Pittaluga, Robert Brink, Danielle L. Fink, Heidi H. Kong, Juraj Kabat, Woo Sung Kim, Tatjana Bierhals, Kazuyuki Meguro, Amy P. Hsu, Jingwen Gu, Jennifer Stoddard, Benito Banos-Pinero, Maria Slack, Giampaolo Trivellin, Benoît Mazel, Maarja Soomann, Samuel Li, Val J. Watts, Constantine A. Stratakis, Maria F. Rodriguez-Quevedo, Ange Line Bruel, Marita Lipsanen-Nyman, Paul Saultier, Rashmi Jain, Daphne Lehalle, Daniel Torres, Kathleen E. Sullivan, Sébastien Barbarot, Axel Neu, Yannis Duffourd, Morgan Similuk, Kirsty McWalter, Pierre Blanc, Stéphane Bézieau, Tian Jin, Raif S. Geha, Jean Laurent Casanova, Outi M. Makitie, Christian Kubisch, Patrick Edery, John Christodoulou, Ronald N. Germain, Christopher C. Goodnow, Thomas P. Sakmar, Daniel D. Billadeau, Sébastien Küry, Vladimir L. Katanaev, Yu Zhang, Michael J. Lenardo, Helen C. Su^*

^*Corresponding author for this work

Human Immunological Diseases Section
National Institutes of Health
Clinical Genomics Program
Division of Oncology Research
Mayo Clinic Rochester, MN
Department of Pathology and Laboratory Medicine
University of Pennsylvania
Department of Cell Physiology and Metabolism
University of Geneva
Laboratory of Chemical Biology and Signal Transduction
Rockefeller University
Advanced Mass Spectrometry Facility
Lung and Vascular Inflammation Section
Lymphocyte Biology Section
Department of Neurology
CNRS UMR 6291
Skeletal Genomics Unit
Laboratory of Clinical Immunology and Microbiology
Biological Imaging Section
Neuronal and Cellular Signal Transduction
University of Hamburg
Institute of Human Genetics
Nationwide Children’s Hospital
Ohio State University
Department of Haematology
The Children's Hospital at Westmead
Division of Human Genetics
Children's Hospital of Philadelphia
Department of Pediatrics
Service de Génétique
Hospices civils de Lyon
Universite Claude Bernard Lyon 1
INSERM U12045 and CHU Rouen
University of Rouen
Bioinformatics and Computational Biosciences Branch
Division of Immunology
University of Zurich
Pediatric Immunology
Neutrophil Monitoring Lab
Leidos Inc
Chemotaxis Signal Section
Division of Pediatric Immunology and Rheumatology
Ludwig Maximilian University of Munich
Department of Pediatrics
Kuwait University
Al-Sabah Hospital
Institute of Human Genetics
Technical University of Munich
Institute of Neurogenomics
Helmholtz Zentrum München - German Research Center for Environmental Health
Division of Laboratories
Utrecht University
Folkhalsan
University of Helsinki
Research Program for Clinical and Molecular Metabolism
APHM
CHU la Timone
Research Unit
Aix-Marseille Université
Oxford University Hospitals NHS Foundation Trust
Genetic Departement
Sorbonne Université
SeqOIA Laboratory
FMG2025
Department of Human Genetics
Radboud University Nijmegen
Department of Molecular and Human Genetics
Baylor College of Medicine
Texas Children's Hospital Houston
Pulmonary Branch
Institut national de la santé et de la recherche médicale
Centre de Génétique et Centre de Référence “Anomalies du Développement et Syndromes Malformatifs de l’Inter-région Est”
Université de Bourgogne
Department of Allergy and Immunology
St. Giles Laboratory of Human Genetics of Infectious Diseases
Laboratory of Human Genetics of Infectious Diseases
INSERM U1163
Université Paris Cité
Division of Immunology
Harvard University
École normale supérieure de Lyon
Oral Immunity and Infection Section
Molecular Development of the Immune System Section
Centre for Population Genomics
University of New South Wales
Murdoch Children's Research Institute
University of Queensland
Illumina, Inc.
Immunogenomics Laboratory
Garvan Institute of Medical Research
School of Clinical Medicine
Laboratory of Pathology
St. Vincent's Hospital Sydney
B Cell Biology Laboratory
Cutaneous Microbiome and Inflammation Section
Immunology Service
Division of Allergy and Immunology
University of Rochester
Purdue University
INSERM
Clinical Immunology
UF de Génétique Clinique
Assistance publique – Hôpitaux de Paris
Division of Allergy and Immunology
Department of Dermatology
Department of Pediatrics
Centralized Sequencing Program
OPKO Health, Inc.
Howard Hughes Medical Institute
Department of Pediatrics
Department of Genetics, Lyon University Hospital, CNRS UMR 5292
Department of Paediatrics
Specialty of Child and Adolescent Health
The University of Sydney

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

29 Citations (Scopus)

Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes G_ai2, 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_ai2 mutations had clinical presentations that included impaired immunity. Mutant G_ai2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G_ai2 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.

Original language	English
Article number	eadd8947
Journal	Science
Volume	385
Issue number	6715
DOIs	https://doi.org/10.1126/science.add8947
Publication status	Published - 20 Sept 2024
Externally published	Yes

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10.1126/science.add8947

Cite this

Ham, H., Jing, H., Lamborn, I. T., Kober, M. M., Koval, A., Berchiche, Y. A., Anderson, D. E., Druey, K. M., Mandl, J. N., Isidor, B., Ferreira, C. R., Freeman, A. F., Ganesan, S., Karsak, M., Mustillo, P. J., Teo, J., Zolkipli-Cunningham, Z., Chatron, N., Lecoquierre, F., ... Su, H. C. (2024). Germline mutations in a G protein identify signaling cross-talk in T cells. Science, 385(6715), Article eadd8947. https://doi.org/10.1126/science.add8947

@article{a3a1579f6d784dcbb8a0fbd31a17d57d,

title = "Germline mutations in a G protein identify signaling cross-talk in T cells",

abstract = "Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gai2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase{\textendash}mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gai2 mutations had clinical presentations that included impaired immunity. Mutant Gai2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gai2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase){\textendash}activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal{\textendash}regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K){\textendash}AKT S6 signaling to drive cellular growth and proliferation.",

author = "Hyoungjun Ham and Huie Jing and Lamborn, \{Ian T.\} and Kober, \{Megan M.\} and Alexey Koval and Berchiche, \{Yamina A.\} and Anderson, \{D. Eric\} and Druey, \{Kirk M.\} and Mandl, \{Judith N.\} and Bertrand Isidor and Ferreira, \{Carlos R.\} and Freeman, \{Alexandra F.\} and Sundar Ganesan and Meliha Karsak and Mustillo, \{Peter J.\} and Juliana Teo and Zarazuela Zolkipli-Cunningham and Nicolas Chatron and Fran{\c c}ois Lecoquierre and Oler, \{Andrew J.\} and Schmid, \{Jana Pachlopnik\} and Kuhns, \{Douglas B.\} and Xuehua Xu and Fabian Hauck and Waleed Al-Herz and Matias Wagner and Terhal, \{Paulien A.\} and Mari Muurinen and Vincent Barlogis and Phillip Cruz and Jeffrey Danielson and Helen Stewart and Petra Loid and Sebastian Rading and Boris Keren and Rolph Pfundt and Zarember, \{Kol A.\} and Katharina Vill and Lorraine Potocki and Olivier, \{Kenneth N.\} and Gaetan Lesca and Laurence Faivre and Melanie Wong and Anne Puel and Janet Chou and Maud Tusseau and Moutsopoulos, \{Niki M.\} and Matthews, \{Helen F.\} and Cas Simons and Taft, \{Ryan J.\} and Ariane Soldatos and Etienne Masle-Farquhar and Stefania Pittaluga and Robert Brink and Fink, \{Danielle L.\} and Kong, \{Heidi H.\} and Juraj Kabat and Kim, \{Woo Sung\} and Tatjana Bierhals and Kazuyuki Meguro and Hsu, \{Amy P.\} and Jingwen Gu and Jennifer Stoddard and Benito Banos-Pinero and Maria Slack and Giampaolo Trivellin and Beno{\^i}t Mazel and Maarja Soomann and Samuel Li and Watts, \{Val J.\} and Stratakis, \{Constantine A.\} and Rodriguez-Quevedo, \{Maria F.\} and Bruel, \{Ange Line\} and Marita Lipsanen-Nyman and Paul Saultier and Rashmi Jain and Daphne Lehalle and Daniel Torres and Sullivan, \{Kathleen E.\} and S{\'e}bastien Barbarot and Axel Neu and Yannis Duffourd and Morgan Similuk and Kirsty McWalter and Pierre Blanc and St{\'e}phane B{\'e}zieau and Tian Jin and Geha, \{Raif S.\} and Casanova, \{Jean Laurent\} and Makitie, \{Outi M.\} and Christian Kubisch and Patrick Edery and John Christodoulou and Germain, \{Ronald N.\} and Goodnow, \{Christopher C.\} and Sakmar, \{Thomas P.\} and Billadeau, \{Daniel D.\} and S{\'e}bastien K{\"u}ry and Katanaev, \{Vladimir L.\} and Yu Zhang and Lenardo, \{Michael J.\} and Su, \{Helen C.\}",

year = "2024",

month = sep,

day = "20",

doi = "10.1126/science.add8947",

language = "English",

volume = "385",

journal = "Science",

issn = "0036-8075",

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

number = "6715",

}

Ham, H, Jing, H, Lamborn, IT, Kober, MM, Koval, A, Berchiche, YA, Anderson, DE, Druey, KM, Mandl, JN, Isidor, B, Ferreira, CR, Freeman, AF, Ganesan, S, Karsak, M, Mustillo, PJ, Teo, J, Zolkipli-Cunningham, Z, Chatron, N, Lecoquierre, F, Oler, AJ, Schmid, JP, Kuhns, DB, Xu, X, Hauck, F, Al-Herz, W, Wagner, M, Terhal, PA, Muurinen, M, Barlogis, V, Cruz, P, Danielson, J, Stewart, H, Loid, P, Rading, S, Keren, B, Pfundt, R, Zarember, KA, Vill, K, Potocki, L, Olivier, KN, Lesca, G, Faivre, L, Wong, M, Puel, A, Chou, J, Tusseau, M, Moutsopoulos, NM, Matthews, HF, Simons, C, Taft, RJ, Soldatos, A, Masle-Farquhar, E, Pittaluga, S, Brink, R, Fink, DL, Kong, HH, Kabat, J, Kim, WS, Bierhals, T, Meguro, K, Hsu, AP, Gu, J, Stoddard, J, Banos-Pinero, B, Slack, M, Trivellin, G, Mazel, B, Soomann, M, Li, S, Watts, VJ, Stratakis, CA, Rodriguez-Quevedo, MF, Bruel, AL, Lipsanen-Nyman, M, Saultier, P, Jain, R, Lehalle, D, Torres, D, Sullivan, KE, Barbarot, S, Neu, A, Duffourd, Y, Similuk, M, McWalter, K, Blanc, P, Bézieau, S, Jin, T, Geha, RS, Casanova, JL, Makitie, OM, Kubisch, C, Edery, P, Christodoulou, J, Germain, RN, Goodnow, CC, Sakmar, TP, Billadeau, DD, Küry, S, Katanaev, VL, Zhang, Y, Lenardo, MJ & Su, HC 2024, 'Germline mutations in a G protein identify signaling cross-talk in T cells', Science, vol. 385, no. 6715, eadd8947. https://doi.org/10.1126/science.add8947

TY - JOUR

T1 - Germline mutations in a G protein identify signaling cross-talk in T cells

AU - Ham, Hyoungjun

AU - Jing, Huie

AU - Lamborn, Ian T.

AU - Kober, Megan M.

AU - Koval, Alexey

AU - Berchiche, Yamina A.

AU - Anderson, D. Eric

AU - Druey, Kirk M.

AU - Mandl, Judith N.

AU - Isidor, Bertrand

AU - Ferreira, Carlos R.

AU - Freeman, Alexandra F.

AU - Ganesan, Sundar

AU - Karsak, Meliha

AU - Mustillo, Peter J.

AU - Teo, Juliana

AU - Zolkipli-Cunningham, Zarazuela

AU - Chatron, Nicolas

AU - Lecoquierre, François

AU - Oler, Andrew J.

AU - Schmid, Jana Pachlopnik

AU - Kuhns, Douglas B.

AU - Xu, Xuehua

AU - Hauck, Fabian

AU - Al-Herz, Waleed

AU - Wagner, Matias

AU - Terhal, Paulien A.

AU - Muurinen, Mari

AU - Barlogis, Vincent

AU - Cruz, Phillip

AU - Danielson, Jeffrey

AU - Stewart, Helen

AU - Loid, Petra

AU - Rading, Sebastian

AU - Keren, Boris

AU - Pfundt, Rolph

AU - Zarember, Kol A.

AU - Vill, Katharina

AU - Potocki, Lorraine

AU - Olivier, Kenneth N.

AU - Lesca, Gaetan

AU - Faivre, Laurence

AU - Wong, Melanie

AU - Puel, Anne

AU - Chou, Janet

AU - Tusseau, Maud

AU - Moutsopoulos, Niki M.

AU - Matthews, Helen F.

AU - Simons, Cas

AU - Taft, Ryan J.

AU - Soldatos, Ariane

AU - Masle-Farquhar, Etienne

AU - Pittaluga, Stefania

AU - Brink, Robert

AU - Fink, Danielle L.

AU - Kong, Heidi H.

AU - Kabat, Juraj

AU - Kim, Woo Sung

AU - Bierhals, Tatjana

AU - Meguro, Kazuyuki

AU - Hsu, Amy P.

AU - Gu, Jingwen

AU - Stoddard, Jennifer

AU - Banos-Pinero, Benito

AU - Slack, Maria

AU - Trivellin, Giampaolo

AU - Mazel, Benoît

AU - Soomann, Maarja

AU - Li, Samuel

AU - Watts, Val J.

AU - Stratakis, Constantine A.

AU - Rodriguez-Quevedo, Maria F.

AU - Bruel, Ange Line

AU - Lipsanen-Nyman, Marita

AU - Saultier, Paul

AU - Jain, Rashmi

AU - Lehalle, Daphne

AU - Torres, Daniel

AU - Sullivan, Kathleen E.

AU - Barbarot, Sébastien

AU - Neu, Axel

AU - Duffourd, Yannis

AU - Similuk, Morgan

AU - McWalter, Kirsty

AU - Blanc, Pierre

AU - Bézieau, Stéphane

AU - Jin, Tian

AU - Geha, Raif S.

AU - Casanova, Jean Laurent

AU - Makitie, Outi M.

AU - Kubisch, Christian

AU - Edery, Patrick

AU - Christodoulou, John

AU - Germain, Ronald N.

AU - Goodnow, Christopher C.

AU - Sakmar, Thomas P.

AU - Billadeau, Daniel D.

AU - Küry, Sébastien

AU - Katanaev, Vladimir L.

AU - Zhang, Yu

AU - Lenardo, Michael J.

AU - Su, Helen C.

PY - 2024/9/20

Y1 - 2024/9/20

N2 - Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gai2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gai2 mutations had clinical presentations that included impaired immunity. Mutant Gai2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gai2 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.

AB - Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gai2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gai2 mutations had clinical presentations that included impaired immunity. Mutant Gai2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gai2 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.

UR - https://www.scopus.com/pages/publications/85204512765

U2 - 10.1126/science.add8947

DO - 10.1126/science.add8947

M3 - Article

C2 - 39298586

AN - SCOPUS:85204512765

SN - 0036-8075

VL - 385

JO - Science

JF - Science

IS - 6715

M1 - eadd8947

ER -

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

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