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Free keywords:
Actins/metabolism
Animals
Bleomycin/toxicity
Cell Movement/*physiology
Cells, Cultured
Cytoskeleton/metabolism/ultrastructure
Extracellular Matrix/metabolism
Female
Fibroblasts/drug effects/metabolism/pathology
Fibrosis/chemically induced/metabolism
Focal Adhesions/physiology
HSP90 Heat-Shock Proteins/genetics/*metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Proteasome Endopeptidase Complex/metabolism
Protein-Serine-Threonine Kinases/genetics/*metabolism
Skin/drug effects/pathology
Ubiquitin-Protein Ligases/genetics/*metabolism
Ubiquitination
Abstract:
Integrin-linked kinase (ILK) is an adaptor protein required to establish and maintain the connection between integrins and the actin cytoskeleton. This linkage is essential for generating force between the extracellular matrix (ECM) and the cell during migration and matrix remodelling. The mechanisms by which ILK stability and turnover are regulated are unknown. Here we report that the E3 ligase CHIP-heat shock protein 90 (Hsp90) axis regulates ILK turnover in fibroblasts. The chaperone Hsp90 stabilizes ILK and facilitates the interaction of ILK with alpha-parvin. When Hsp90 activity is blocked, ILK is ubiquitinated by CHIP and degraded by the proteasome, resulting in impaired fibroblast migration and a dramatic reduction in the fibrotic response to bleomycin in mice. Together, our results uncover how Hsp90 regulates ILK stability and identify a potential therapeutic strategy to alleviate fibrotic diseases.
