JNK1 participates in the VHL-independent HIF-1α degradation pathway by regulating Hsp90/Hsp70 turnover and the HDAC6-dependent chaperone activity

摘要

Hypoxia induced factor-1α (HIF-1α) is a master transcription factor that is critical for the regulation of various cellular functions. HIF-1α is rapidly degraded via a von Hippel-Lindau tumor suppressor gene product (VHL)-mediated ubiquitin-proteasome pathway in normoxia conditions. Most recent studies reveal that heat-shock proteins (Hsp) can regulate HIF-1α protein degradation via a VHL-independent pathway. Here we demonstrate that c-Jun N-terminal kinase 1 (JNK1) is required for such an Hsp-dependent HIF-1α regulation. HIF-1α stabilization was impaired in JNK1−/− cells, and could be rescued by reconstitutional expression of JNK1 in either hypoxia or chemical-mimicked hypoxia conditions. This phenomena was confirmed in different cell lines using the shRNA-JNK1 knockdown approach. Accordingly, HIF-1-dependent transcriptional activity and its downstream gene’s expression were dramatically reduced in JNK1-deficient cells. We further found that in JNK1−/− cells the low expression level of Hsp90/Hsp70 proteins affected the protective roles of these chaperones in maintaining newly synthesized HIF-1α stabilization, and forced expression of Hsp90 or Hsp70 in JNK1−/− cells showed a notable increase in HIF-1α stability compared with that of parental cells. Furthermore, our studies found that defective HDAC6 expression and subsequently increased Hsp90 acetylation could account for the reduction of Hsp90 chaperon activity in JNK1−/− cells. Taken together, our studies provide strong evidence for a novel function of JNK1 in regulating VHL-independent HIF-1α degradation.