AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

Nat Commun. 2020 Feb 25;11(1):1032. doi: 10.1038/s41467-020-14812-0.

Abstract

The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Beclin-1 / metabolism
  • Biphenyl Compounds
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / genetics
  • Cyclins / metabolism*
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation / drug effects
  • Protein Array Analysis
  • Pyrones / pharmacology
  • Serine / metabolism
  • Thiophenes / pharmacology

Substances

  • Beclin-1
  • Biphenyl Compounds
  • CCNY protein, human
  • Cyclins
  • Intracellular Signaling Peptides and Proteins
  • Pyrones
  • Thiophenes
  • Serine
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human
  • CDK14 protein, human
  • CDK15 protein, human
  • Cyclin-Dependent Kinases
  • PCTAIRE-1 protein kinase
  • AMP-Activated Protein Kinases
  • 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile