Glycolysis promotes caspase-3 activation in lipid rafts in T cells.


Type
Article
Change log
Authors
Secinaro, Michael A 
Fortner, Karen A 
Dienz, Oliver 
Logan, Angela 
Murphy, Michael P 
Abstract

Resting T cells undergo a rapid metabolic shift to glycolysis upon activation in the presence of interleukin (IL)-2, in contrast to oxidative mitochondrial respiration with IL-15. Paralleling these different metabolic states are striking differences in susceptibility to restimulation-induced cell death (RICD); glycolytic effector T cells are highly sensitive to RICD, whereas non-glycolytic T cells are resistant. It is unclear whether the metabolic state of a T cell is linked to its susceptibility to RICD. Our findings reveal that IL-2-driven glycolysis promotes caspase-3 activity and increases sensitivity to RICD. Neither caspase-7, caspase-8, nor caspase-9 activity is affected by these metabolic differences. Inhibition of glycolysis with 2-deoxyglucose reduces caspase-3 activity as well as sensitivity to RICD. By contrast, IL-15-driven oxidative phosphorylation actively inhibits caspase-3 activity through its glutathionylation. We further observe active caspase-3 in the lipid rafts of glycolytic but not non-glycolytic T cells, suggesting a proximity-induced model of self-activation. Finally, we observe that effector T cells during influenza infection manifest higher levels of active caspase-3 than naive T cells. Collectively, our findings demonstrate that glycolysis drives caspase-3 activity and susceptibility to cell death in effector T cells independently of upstream caspases. Linking metabolism, caspase-3 activity, and cell death provides an intrinsic mechanism for T cells to limit the duration of effector function.

Description
Keywords
Caspase 3, Glycolysis, Humans, T-Lymphocytes
Journal Title
Cell Death Dis
Conference Name
Journal ISSN
2041-4889
2041-4889
Volume Title
9
Publisher
Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_U105663142)
Medical Research Council (MC_UU_00015/3)
Wellcome Trust (110159/Z/15/Z)