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. 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

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. 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

Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu

Abstrakti

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.

Alkuperäiskieli	englanti
Artikkeli	eadd8947
Lehti	Science (New York, N.Y.)
Vuosikerta	385
Numero	6715
Sivumäärä	18
ISSN	0036-8075
DOI - pysyväislinkit	https://doi.org/10.1126/science.add8947
Tila	Julkaistu - 20 syysk. 2024
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

3111 Biolääketieteet

Pääsy asiakirjaan

10.1126/science.add8947

Siteeraa tätä

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 (New York, N.Y.), 385(6715), Artikkeli eadd8947. https://doi.org/10.1126/science.add8947

@article{93cfe192b5784a88b24b3f0a48d49286,

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 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.",

keywords = "3111 Biomedicine",

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 M{\"a}kitie, {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 (New York, N.Y.)",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science (AAAS)",

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, Mäkitie, 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 (New York, N.Y.), Vuosikerta 385, Nro 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 - Mäkitie, 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 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.

AB - 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.

KW - 3111 Biomedicine

U2 - 10.1126/science.add8947

DO - 10.1126/science.add8947

M3 - Article

C2 - 39298586

AN - SCOPUS:85204512765

SN - 0036-8075

VL - 385

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6715

M1 - eadd8947

ER -