Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria

Joachim Lauterwasser, Franziska Fimm-Todt, Aline Oelgeklaus, Annabell Schreiner, Kathrin Funk, Hugo Falquez-Medina, Ramona Klesse, Günther Jahreis, Ralf M. Zerbes, Katelyn O'Neill, Martin van der Laan, Xu Luo, Frank Edlich

Research output: Contribution to journalArticlepeer-review

Abstract

Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.

Original languageEnglish (US)
Article numbere2021175118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number33
DOIs
StatePublished - Aug 17 2021

Keywords

  • Apoptosis
  • BCL-2 proteins
  • BH3-only proteins

ASJC Scopus subject areas

  • General

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