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
Volume9
Issue2
Pagination62
Date Published2018 Jan 19
ISSN2041-4889
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.

DOI10.1038/s41419-017-0099-z
Alternate JournalCell Death Dis
Citation Key10.1038/s41419-017-0099-z
PubMed ID29352186
Grant ListR01 HL122383 / HL / NHLBI NIH HHS / United States