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Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells

Bantug, Glenn R. and Fischer, Marco and Grählert, Jasmin and Balmer, Maria L. and Unterstab, Gunhild and Develioglu, Leyla and Steiner, Rebekah and Zhang, Lianjun and Costa, Ana S. H. and Gubser, Patrick M. and Burgener, Anne-Valérie and Sauder, Ursula and Löliger, Jordan and Belle, Réka and Dimeloe, Sarah and Lötscher, Jonas and Jauch, Annaïse and Recher, Mike and Hönger, Gideon and Hall, Michael N. and Romero, Pedro and Frezza, Christian and Hess, Christoph. (2018) Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells. Immunity, 48 (3). pp. 542-555.

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Abstract

Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3β at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1074-7613
e-ISSN:1097-4180
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:23 Mar 2018 14:57
Deposited On:23 Mar 2018 14:57

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