Germline mutations in a G protein identify signaling cross-talk in T cells.
Hyoungjun HamHuie JingIan T LambornMegan M KoberAlexey KovalYamina A BerchicheD Eric AndersonKirk M DrueyJudith N MandlBertrand IsidorCarlos R FerreiraAlexandra F FreemanSundar GanesanMeliha KarsakPeter J MustilloJuliana TeoZarazuela Zolkipli-CunninghamNicolas ChatronFrancois LecoquierreAndrew J OlerJana Pachlopnik SchmidDouglas B KuhnsXuehua XuFabian H HauckWaleed Al HerzMatias WagnerPaulien Anna TerhalMari MuurinenVincent BarlogisPhillip CruzJeffrey DanielsonHelen StewartPetra LoidSebastian RadingBoris KerenRolph PfundtKol A ZaremberKatharina VillLorraine PotockiKenneth N OlivierGaëtan LescaLaurence Olivier-FaivreMelanie WongAnne PuelJanet ChouMaud TusseauNiki M MoutsopoulosHelen F MatthewsCas SimonsRyan J TaftAriane G SoldatosEtienne Masle-FarquharStefania PittalugaRobert BrinkDanielle L FinkHeidi H KongJuraj KabatWoo Sung KimTatjana BierhalsKazuyuki MeguroAmy P HsuJingwen GuJennifer StoddardBenito Banos-PineroMaria SlackGiampaolo TrivellinBenoit MazelMaarja SoomannSamuel LiVal J WattsConstantine A StratakisMaria F Rodriguez-QuevedoAnge-Line BruelMarita Lipsanen-NymanPaul SaultierRashmi JainDaphne LehalleDaniel TorresKathleen E SullivanSébastien BarbarotAxel NeuYannis DuffourdMorgan N SimilukKirsty McWalterPierre BlancStephane BezieauTian JinRaif S GehaJean Laurent CasanovaOutimaija MäkitieChristian KubischPatrick EderyJohn ChrisodoulouRonald N GermainChristopher C GoodnowThomas P SakmarDaniel D BilladeauSébastien KüryVladimir L KatanaevYu ZhangMichael J LenardoHelen C SuPublished in: Science (New York, N.Y.) (2024)
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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