AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

Mol Pharmacol. 2016 Oct;90(4):460-8. doi: 10.1124/mol.116.105494. Epub 2016 Jul 18.

Abstract

Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 5'-AMP-activated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic conditions. Here, we dissected the role of AMPK for oxidant-induced SG formation. Our studies identified multiple steps of de novo SG assembly that are controlled by the kinase. Single-cell analyses demonstrated that pharmacological AMPK activation prior to stress exposure changed SG properties, because the granules became more abundant and smaller in size. These altered SG characteristics correlated with specific changes in cell survival, cell signaling, cytoskeletal organization, and the abundance of translation initiation factors. Specifically, AMPK activation increased stress-induced eukaryotic initiation factor (eIF) 2α phosphorylation and reduced the concentration of eIF4F complex subunits eIF4G and eIF4E. At the same time, the abundance of histone deacetylase 6 (HDAC6) was diminished. This loss of HDAC6 was accompanied by increased acetylation of α-tubulin on Lys40. Pharmacological studies further confirmed this novel AMPK-HDAC6 interplay and its importance for SG biology. Taken together, we provide mechanistic insights into the regulation of SG formation. We propose that AMPK activation stimulates oxidant-induced SG formation but limits their fusion into larger granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Survival / drug effects
  • Cytoplasmic Granules / drug effects
  • Cytoplasmic Granules / metabolism*
  • Enzyme Activation / drug effects
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factor-4G / metabolism
  • HeLa Cells
  • Histone Deacetylases / metabolism
  • Humans
  • Maleates / pharmacology
  • Mice
  • Microtubules / drug effects
  • Microtubules / metabolism*
  • Models, Biological
  • Oxidants / toxicity*
  • Phosphorylation
  • Pyrones / pharmacology
  • Signal Transduction / drug effects*
  • Stress, Physiological / drug effects
  • Thiophenes / pharmacology
  • rho-Associated Kinases / metabolism

Substances

  • A 769662
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Maleates
  • Oxidants
  • Pyrones
  • Thiophenes
  • rho-Associated Kinases
  • AMP-Activated Protein Kinases
  • Histone Deacetylases
  • diethyl maleate