RACK1 vs. HSP90: Competition for HIF-1α degradation vs. stabilization

Oxygen homeostasis represents an essential organizing principle of metazoan evolution and biology. Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O₂ concentration. HIF-1 is a heterodimeric transcription factor that consists of HIF-1α and HIF-1β subunits. O₂-dependent degradation of the HIF-1α subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/ Elongin-B E3 ubiquitin ligase, and the proteasome. Inhibitors of heat shock protein 90 (HSP90) dissociate HSP90 from HIF-1α and induce O ₂/PHD/VHL-independent degradation of HIF-1α. Recently, we reported the identification of receptor of activated protein C kinase (RACK1) as a novel HIF-1α interacting protein. RACK1 promotes the O ₂/PHD/VHL-independent and proteasome-dependent degradation of HIF-1α. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1α. RACK1 activity is required for the mechanism of action for the HSP90 inhibitor 17-allylaminogeldanamycin to induce HIF-1α degradation. RACK1 binds to Elongin-C and recruits Elongin-B and other components of E3 ubiquitin ligase to HIF-1α. The ubiquitination and degradation of HIF-1α are promoted by RACK1. RACK1 is an essential component of an O ₂/PHD/VHL-independent system for regulating HIF-1α stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex. Here we discuss how this system may be regulated.