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 α-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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Actins / metabolism
-
Animals
-
Bleomycin / toxicity
-
Cell Movement / physiology*
-
Cells, Cultured
-
Cytoskeleton / metabolism
-
Cytoskeleton / ultrastructure
-
Extracellular Matrix / metabolism
-
Female
-
Fibroblasts / drug effects
-
Fibroblasts / metabolism
-
Fibroblasts / pathology
-
Fibrosis / chemically induced
-
Fibrosis / metabolism
-
Focal Adhesions / physiology
-
HSP90 Heat-Shock Proteins / genetics
-
HSP90 Heat-Shock Proteins / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Mutant Strains
-
Proteasome Endopeptidase Complex / metabolism
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
Skin / drug effects
-
Skin / pathology
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Ubiquitination
Substances
-
Actins
-
HSP90 Heat-Shock Proteins
-
Bleomycin
-
Stub1 protein, mouse
-
Ubiquitin-Protein Ligases
-
integrin-linked kinase
-
Protein Serine-Threonine Kinases
-
Proteasome Endopeptidase Complex