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Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs
that Orchestrate the Rapid Recall Response of Memory CD8(+) T Cells
#MMPMID29523440
Bantug GR
; Fischer M
; Grählert J
; Balmer ML
; Unterstab G
; Develioglu L
; Steiner R
; Zhang L
; Costa ASH
; Gubser PM
; Burgener AV
; Sauder U
; Löliger J
; Belle R
; Dimeloe S
; Lötscher J
; Jauch A
; Recher M
; Hönger G
; Hall MN
; Romero P
; Frezza C
; Hess C
Immunity
2018[Mar]; 48
(3
): 542-555.e6
PMID29523440
show ga
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 3?
(GSK3?) 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-? (IFN-?) in memory T cells. Subcellular organization of
mTORC2-AKT-GSK3? 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.
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