Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy

Ruth Shiloh, Yuval Gilad, Yaara Ber, Miriam Eisenstein, Dina Aweida, Shani Bialik, Shenhav Cohen, Adi Kimchi

Research output: Contribution to journalArticlepeer-review


Autophagy is an intracellular degradation process essential for adaptation to metabolic stress. DAPK2 is a calmodulin-regulated protein kinase, which has been implicated in autophagy regulation, though the mechanism is unclear. Here, we show that the central metabolic sensor, AMPK, phosphorylates DAPK2 at a critical site in the protein structure, between the catalytic and the calmodulin-binding domains. This phosphorylation activates DAPK2 by functionally mimicking calmodulin binding and mitigating an inhibitory autophosphorylation, providing a novel, alternative mechanism for DAPK2 activation during metabolic stress. In addition, we show that DAPK2 phosphorylates the core autophagic machinery protein, Beclin-1, leading to dissociation of its inhibitor, Bcl-X-L. Importantly, phosphorylation of DAPK2 by AMPK enhances DAPK2's ability to phosphorylate Beclin-1, and depletion of DAPK2 reduces autophagy in response to AMPK activation. Our study reveals a unique calmodulin-independent mechanism for DAPK2 activation, critical to its function as a novel downstream effector of AMPK in autophagy.

Original languageEnglish
Article number1759
Number of pages15
JournalNature Communications
Issue number1
StatePublished - 1 May 2018

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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