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MAPK- and glycogen synthase kinase 3-mediated phosphorylation regulates the
DEAD-box protein modulator Gle1 for control of stress granule dynamics.
Authors Aditi, Mason AC, Sharma M, Dawson TR, Wente SR
Submitted By Submitted Externally on 2/22/2019
Status Published
Journal The Journal of biological chemistry
Year 2019
Date Published 1/11/2019
Volume : Pages 294 : 559 - 575
PubMed Reference 30429220
Abstract Rapid expression of critical stress response factors is a key survival strategy
for diseased or stressed cells. During cell stress, translation is inhibited,
and a pre-existing pool of cytoplasmic mRNA-protein complexes reversibly
assembles into cytoplasmic stress granules (SGs). Gle1 is a conserved modulator
of RNA-dependent DEAD-box proteins required for mRNA export, translation, and
stress responses. Proper Gle1 function is critical as reflected by some human
diseases such as developmental and neurodegenerative disorders and some cancers
linked to gle1 mutations. However, the mechanism by which Gle1 controls SG
formation is incompletely understood. Here, we show that human Gle1 is regulated
by phosphorylation during heat shock stress. In HeLa cells, stress-induced Gle1
hyperphosphorylation was dynamic, primarily in the cytoplasmic pool, and
followed changes in translation factors. MS analysis identified 14
phosphorylation sites in the Gle1A isoform, six of which clustered in an
intrinsically disordered, low-complexity N-terminal region flanking the
coil-coiled self-association domain. Of note, two mitogen-activated protein
kinases (MAPKs), extracellular signal-regulated kinase (ERK) and c-Jun
N-terminal kinase (JNK), phosphorylated the Gle1A N-terminal domain, priming it
for phosphorylation by glycogen synthase kinase 3 (GSK3). A phosphomimetic
gle1A6D variant (in which six putative Ser/Thr phosphorylation sites were
substituted with Asp) perturbed self-association and inhibited DEAD-box helicase
3 (X-linked) (DDX3) ATPase activity. Expression of alanine-substituted,
phosphodeficient GFP-gle1A6A promoted SG assembly, whereas GFP-gle1A6D enhanced
SG disassembly. We propose that MAPKs and GSK3 phosphorylate Gle1A and thereby
coordinate SG dynamics by altering DDX3 function.


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