title: Hsp27 and F-box protein β-TrCP promote degradation of mRNA decay factor AUF1.
abstract: Activation of the mitogen-activated protein (MAP) pathway kinases p38 and MK2 induces phosphorylation of the chaperone Hsp27 and stabilization of mRNAs containing AU-rich elements (AREs) (ARE-mRNAs). Likewise, expression of phosphomimetic mutant forms of Hsp27 also stabilizes ARE-mRNAs. It appears to perform this function by promoting degradation of the ARE-mRNA decay factor AUF1 by proteasomes. In this study, we examined the molecular mechanism linking Hsp27 phosphorylation to AUF1 degradation by proteasomes. AUF1 is a target of β-TrCP, the substrate recognition subunit of the E3 ubiquitin ligase Skp1-cullin-F-box protein complex, SCF(β-TrCP). Depletion of β-TrCP stabilized AUF1. In contrast, overexpression of β-TrCP enhanced ubiquitination and degradation of AUF1 and led to stabilization of reporter mRNAs containing cytokine AREs. Enhanced AUF1 degradation required expression of phosphomimetic mutant forms of both Hsp27 and AUF1. Our results suggest that a signaling axis composed of p38 MAP kinase-MK2-Hsp27-β-TrCP may promote AUF1 degradation by proteasomes and stabilization of cytokine ARE-mRNAs.
authors.affiliation: Department of Biochemistry & Molecular Biology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Defren
authors.forename: Gary
authors.initials: G
authors.lastname: Brewer
mesh_terms: D063307:AU Rich Elements; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D015398:Signal Transduction; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: 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; D018832:Molecular Chaperones; D044844:beta-Transducin Repeat-Containing Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex