Chaperone Hsp27 modulates AUF1 proteolysis and AU-rich element-mediated mRNA degradation.
AUF1 is an AU-rich element (ARE)-binding protein that recruits translation initiation factors, molecular chaperones, and mRNA degradation enzymes to the ARE for mRNA destruction. We recently found chaperone Hsp27 to be an AUF1-associated ARE-binding protein required for tumor necrosis factor alpha (TNF-α) mRNA degradation in monocytes. Hsp27 is a multifunctional protein that participates in ubiquitination of proteins for their degradation by proteasomes. A variety of extracellular stimuli promote Hsp27 phosphorylation on three serine residues--Ser(15), Ser(78), and Ser(82)-by a number of kinases, including the mitogen-activated protein (MAP) pathway kinases p38 and MK2. Activating either kinase stabilizes ARE mRNAs. Likewise, ectopic expression of phosphomimetic mutant forms of Hsp27 stabilizes reporter ARE mRNAs. Here, we continued to examine the contributions of Hsp27 to mRNA degradation. As AUF1 is ubiquitinated and degraded by proteasomes, we addressed the hypothesis that Hsp27 phosphorylation controls AUF1 levels to modulate ARE mRNA degradation. Indeed, selected phosphomimetic mutants of Hsp27 promote proteolysis of AUF1 in a proteasome-dependent fashion and render ARE mRNAs more stable. Our results suggest that the p38 MAP kinase (MAPK)-MK2-Hsp27 signaling axis may target AUF1 destruction by proteasomes, thereby promoting ARE mRNA stabilization.
Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
Anna M
AM
Knapinska
Frances M
FM
Gratacós
Christopher D
CD
Krause
Kristina
K
Hernandez
Amber G
AG
Jensen
Jacquelyn J
JJ
Bradley
Xiangyue
X
Wu
Sidney
S
Pestka
Gary
G
Brewer
D019943:Amino Acid Substitution / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival; D031541:Fluorescence Resonance Energy Transfer; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D053583:Interleukin-1beta / Q000235:genetics; D007700:Kinetics; D018832:Molecular Chaperones; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D020871:RNA Stability / Q000235:genetics*; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C000630986:HNRNPD protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D053583:Interleukin-1beta; D018832:Molecular Chaperones; D050505:Mutant Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D014409:Tumor Necrosis Factor-alpha; D046988:Proteasome Endopeptidase Complex
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