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. OlerJana 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. Mäkitie, 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

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 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 languageEnglish
Article numbereadd8947
JournalScience (New York, N.Y.)
Volume385
Issue number6715
Number of pages18
ISSN0036-8075
DOIs
Publication statusPublished - 20 Sept 2024
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine

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