The Chaperone-Dependent Ubiquitin Ligase CHIP Targets HIF-1α for Degradation in the Presence of Methylglyoxal

Hypoxia-inducible factor-1 (HIF-1) plays a key role in cell adaptation to low oxygen and stabilization of HIF-1 is vital to ensure cell survival under hypoxia. Diabetes has been associated with impairment of the cell response to hypoxia and downregulation of HIF-1 is most likely the event that transduces hyperglycemia into increased cell death in diabetes-associated hypoxia. In this study, we aimed at identifying the molecular mechanism implicated in destabilization of HIF-1 by high glucose. In this work, we identified a new molecular mechanism whereby methylglyoxal (MGO), which accumulates in high-glucose conditions, led to a rapid proteasome-dependent degradation of HIF-1 alpha under hypoxia. Significantly, MGO-induced degradation of HIF-1 alpha did not require the recruitment of the ubiquitin ligase pVHL nor did it require hydroxylation of the proline residues P402/P564 of HIF-1 alpha. Moreover, we identified CHIP (Carboxy terminus of Hsp70-Interacting Protein) as the E3 ligase that ubiquitinated HIF-1 alpha in the presence of MGO. Consistently, silencing of endogenous CHIP and overexpression of glyoxalase I both stabilized HIF-1 alpha under hypoxia in the presence of MGO. Data shows that increased association of Hsp40/70 with HIF-1 alpha led to recruitment of CHIP, which promoted polyubiquitination and degradation of HIF-1 alpha. Moreover, MGO-induced destabilization of HIF-1 alpha led to a dramatic decrease in HIF-1 transcriptional activity. Altogether, data is consistent with a new pathway for degradation of HIF-1 alpha in response to intracellular accumulation of MGO. Moreover, we suggest that accumulation of MGO is likely to be the link between high glucose and the loss of cell response to hypoxia in diabetes.