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