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 and Adi Kimchi ()
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Ruth Shiloh: Weizmann Institute of Science
Yuval Gilad: Weizmann Institute of Science
Yaara Ber: Weizmann Institute of Science
Miriam Eisenstein: Weizmann Institute of Science
Dina Aweida: Technion Israel Institute of Technology
Shani Bialik: Weizmann Institute of Science
Shenhav Cohen: Technion Israel Institute of Technology
Adi Kimchi: Weizmann Institute of Science

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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-XL. 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.

Date: 2018
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DOI: 10.1038/s41467-018-03907-4

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