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J Biol Chem. 2008 Sep 12;283(37):25348-55. doi: 10.1074/jbc.M801635200. Epub 2008 Jul 10.

Ubiquitin-proteasome-mediated degradation of keratin intermediate filaments in mechanically stimulated A549 cells.

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  • 1Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, 240 East Huron, Chicago, IL 60611, USA.

Abstract

We previously reported that shear stress induces phosphorylation and disassembly of keratin intermediate filaments (IFs). Shear stress also induces a time- and strain-dependent degradation of keratin IFs, and the current study examines the mechanisms involved in degradation of keratin proteins in human A549 cells exposed to 0-24 h of shear stress (7.5-30 dynes/cm(2)). Ubiquitin was found to be covalently associated with keratin proteins immunoprecipitated from shear-stressed cells, and pretreatment with the proteasomal inhibitor MG132 prevented the degradation of the keratin IF network. Importantly, phosphorylation of K8 Ser-73 is required for the shear stress-mediated ubiquitination, disassembly, and degradation of the keratin IF network. Immunofluorescence microscopy revealed that shear stress caused the thin array of keratin fibrils observed in control cells to be reorganized into a perinuclear aggregate, known as an aggresome, and that ubiquitin was also associated with this structure. Finally, the E2 enzymes, UbcH5b, -c, and Ubc3, but not E2-25K are required for the shear stress-mediated ubiquitin-proteasomal degradation of keratin proteins. These data suggest that shear stress promotes the disassembly and degradation of the keratin IF network via phosphorylation and the ubiquitin-proteasome pathway.

PMID:
18617517
[PubMed - indexed for MEDLINE]
PMCID:
PMC2533078
Free PMC Article

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