title: Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response.
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.
authors.affiliation: Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
authors.forename: Korana
authors.initials: K
authors.lastname: Radovanac
authors.forename: Jessica
authors.initials: J
authors.lastname: Morgner
authors.forename: Jan-Niklas
authors.initials: JN
authors.lastname: Schulz
authors.forename: Katrin
authors.initials: K
authors.lastname: Blumbach
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Tamar
authors.initials: T
authors.lastname: Geiger
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Beate
authors.initials: B
authors.lastname: Eckes
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Sara A
authors.initials: SA
authors.lastname: Wickström
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D022001:Focal Adhesions / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D001761:Bleomycin; D018841:HSP90 Heat-Shock Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099200:Scaffold Protein ILK; C492951:Stub1 protein, mouse