Syntaxin11 deficiency inhibits CRAC channel priming to suppress cytotoxicity and gene expression in T lymphocytes independent of membrane trafficking.
6 affiliations
- 1Tata Institute of Fundamental Research, Hyderabad, India.
- 2National Centre for Biological Sciences, Bangalore, India.
- 3Northwestern University, Feinberg School of Medicine, Chicago, United States.
- 4Institute for Immunodeficiency, University of Freiburg, Freiburg im Breisgau, Germany.
- 5Institute for Transfusion Medicine and Gene Therapy, University of Freiburg, Freiburg im Breisgau, Germany.
- 6Dr. Shahrooei Lab, Tehran, Iran.
Abstract
Mutations in Syntaxin11 (STX11), a Q-SNARE, result in a fatal immune disorder known as familial hemophagocytic lymphohistiocytosis 4 (FHLH4) in human patients. A key diagnostic feature of FHLH4 is defective T and natural killer cell cytotoxicity. Here, we show that STX11 directly binds and regulates Orai1, the pore-forming subunit of calcium release-activated calcium (CRAC) channels. CRAC channels enable store-operated calcium entry (SOCE) from the extracellular space and are crucial for granule exocytosis and nuclear factor of activated T cells (NFAT)-dependent gene expression in activated lymphocytes. STX11 depletion strongly inhibited SOCE, CRAC currents, NFAT activation, interleukin-2 gene expression, and degranulation in FHLH4 patient T lymphocytes and cell lines without affecting membrane trafficking. Remarkably, defects of cytolytic granule exocytosis, as well as interleukin-2 expression, could be reversed by ionomycin in patient T lymphocytes, and a constitutively active, H134S, mutant of Orai1 rescued calcium entry in STX11-depleted cells. Further analyses showed that STX11 'primes' Orai1 for optimal on-site multimeric assembly, which was Stim independent but required for gating. Priming of ion channel pore subunits is, therefore, a primary function of specific SNAREs which may have preceded their role in membrane trafficking and vesicle fusion.
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BibTeX
@article{datta2026syntaxin11,
title = {{Syntaxin11 deficiency inhibits CRAC channel priming to suppress cytotoxicity and gene expression in T lymphocytes independent of membrane trafficking.}},
author = {Sritama Datta and Abhikarsh Gupta and Kunal M Jagetiya and Resmi Bera and Vikas R Tiwari and Megumi Yamashita and Atharva R Yande and Abdul Rishad and Vishal Malik and Sreejith Raran-Kurussi and Sandra Ammann and Mohammad Shahrooei and Kalyaneswar Mandal and Ramanathan Sowdhamini and Murali Prakriya and Adish Dani and Monika Vig},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.111335},
url = {https://europepmc.org/article/MED/42895167},
note = {CC BY},
}
RIS
TY - JOUR
TI - Syntaxin11 deficiency inhibits CRAC channel priming to suppress cytotoxicity and gene expression in T lymphocytes independent of membrane trafficking.
AU - Sritama Datta
AU - Abhikarsh Gupta
AU - Kunal M Jagetiya
AU - Resmi Bera
AU - Vikas R Tiwari
AU - Megumi Yamashita
AU - Atharva R Yande
AU - Abdul Rishad
AU - Vishal Malik
AU - Sreejith Raran-Kurussi
AU - Sandra Ammann
AU - Mohammad Shahrooei
AU - Kalyaneswar Mandal
AU - Ramanathan Sowdhamini
AU - Murali Prakriya
AU - Adish Dani
AU - Monika Vig
PY - 2026
DA - 2026/10/19
JO - ELife
DO - 10.7554/elife.111335
UR - https://europepmc.org/article/MED/42895167
AB - Mutations in Syntaxin11 (STX11), a Q-SNARE, result in a fatal immune disorder known as familial hemophagocytic lymphohistiocytosis 4 (FHLH4) in human patients. A key diagnostic feature of FHLH4 is defective T and natural killer cell cytotoxicity. Here, we show that STX11 directly binds and regulates Orai1, the pore-forming subunit of calcium release-activated calcium (CRAC) channels. CRAC channels enable store-operated calcium entry (SOCE) from the extracellular space and are crucial for granule exocytosis and nuclear factor of activated T cells (NFAT)-dependent gene expression in activated lymphocytes. STX11 depletion strongly inhibited SOCE, CRAC currents, NFAT activation, interleukin-2 gene expression, and degranulation in FHLH4 patient T lymphocytes and cell lines without affecting membrane trafficking. Remarkably, defects of cytolytic granule exocytosis, as well as interleukin-2 expression, could be reversed by ionomycin in patient T lymphocytes, and a constitutively active, H134S, mutant of Orai1 rescued calcium entry in STX11-depleted cells. Further analyses showed that STX11 'primes' Orai1 for optimal on-site multimeric assembly, which was Stim independent but required for gating. Priming of ion channel pore subunits is, therefore, a primary function of specific SNAREs which may have preceded their role in membrane trafficking and vesicle fusion.
SN - 2050-084X
ER -