Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response

TY - JOUR

T1 - Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response

AU - Radovanac, Korana

AU - Morgner, Jessica

AU - Schulz, Jan-Niklas

AU - Blumbach, Katrin

AU - Patterson, Cam

AU - Geiger, Tamar

AU - Mann, Matthias

AU - Krieg, Thomas

AU - Eckes, Beate

AU - Fässler, Reinhard

AU - Wickström, Sara A

PY - 2013/5/15

Y1 - 2013/5/15

N2 - 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.

AB - 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.

KW - Actins

KW - Animals

KW - Bleomycin

KW - Cell Movement

KW - Cells, Cultured

KW - Cytoskeleton

KW - Extracellular Matrix

KW - Female

KW - Fibroblasts

KW - Fibrosis

KW - Focal Adhesions

KW - HSP90 Heat-Shock Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Proteasome Endopeptidase Complex

KW - Protein-Serine-Threonine Kinases

KW - Skin

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

U2 - 10.1038/emboj.2013.90

DO - 10.1038/emboj.2013.90

M3 - Journal article

C2 - 23612611

SN - 0261-4189

VL - 32

SP - 1409

EP - 1424

JO - E M B O Journal

JF - E M B O Journal

IS - 10

ER -