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AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization
- Source :
- Molecular pharmacology. 90(4)
- Publication Year :
- 2016
-
Abstract
- [Figure][1] 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) 2 α 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. [1]: pending:yes
- Subjects :
- 0301 basic medicine
Cell signaling
Cell Survival
Eukaryotic Initiation Factor-2
Thiophenes
Biology
AMP-Activated Protein Kinases
Cytoplasmic Granules
Microtubules
Models, Biological
Histone Deacetylases
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Stress granule
Stress, Physiological
Eukaryotic initiation factor
Animals
Humans
Phosphorylation
Protein kinase A
Pharmacology
rho-Associated Kinases
EIF4G
EIF4E
Biphenyl Compounds
Maleates
AMPK
HDAC6
Oxidants
Cell biology
Enzyme Activation
030104 developmental biology
Eukaryotic Initiation Factor-4E
chemistry
Pyrones
030220 oncology & carcinogenesis
Molecular Medicine
Eukaryotic Initiation Factor-4G
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 15210111
- Volume :
- 90
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Molecular pharmacology
- Accession number :
- edsair.doi.dedup.....e12d911ffa2a14a1e7c3e6dc1ee16001