CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins.
作者： Howard Doong , Kathryn Rizzo , Shengyun Fang , Vyta Kulpa , Allan M. Weissman
关键词:
摘要: BAG family proteins are regulatory co-chaperones for heat shock protein (Hsp) 70. Hsp70 facilitates the removal of injured by ubiquitin-mediated proteasomal degradation. This process can be driven geldanamycin, an irreversible blocker Hsp90. We hypothesize that CAIR-1/BAG-3 inhibits Hsp-mediated Human breast cancer cells were engineered to overexpress either full-length CAIR-1 (FL), which binds Hsp70, or a domain-deletion mutant (dBAG) cannot bind Hsp70. FL overexpression prevented geldanamycin-mediated loss total and phospho-Akt other Hsp client proteins. dBAG provided no protection, indicating requirement binding. Ubiquitinated Akt accumulated in FL-expressing cells, mimicking effect lactacystin inhibition, degradation distal ubiquitination domain-dependent manner. Protein protection was generalizable downstream targets, GSK3β, P70S6 kinase, CREB, proteins, including Raf-1, cyclin-dependent kinase 4, epidermal growth factor receptor. These findings suggest is chaperone driving multiprotein complex inhibitory co-chaperone functions ubiquitination. Furthermore, poly-ubiquitination not sufficient efficient targeting
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