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

TitleGlycolysis promotes caspase-3 activation in lipid rafts in T cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsSecinaro, MA, Fortner, KA, Dienz, O, Logan, A, Murphy, MP, Anathy, V, Boyson, JE, Budd, RC
JournalCell Death Dis
Date Published2018 Jan 19

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.

Alternate JournalCell Death Dis
Citation Key10.1038/s41419-017-0099-z
PubMed ID29352186
Grant ListR01 HL122383 / HL / NHLBI NIH HHS / United States