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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-09-20 DOI:10.1126/science.add8947

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

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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.

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一种 G 蛋白的基因突变发现了 T 细胞中的信号交叉。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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