Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/110213
Title: The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal
Authors: Bento, Carla Figueira 
Fernandes, Rosa 
Ramalho, José 
Marques, Carla 
Shang, Fu 
Taylor, Allen 
Pereira, Paulo 
Issue Date: 29-Nov-2010
Publisher: Public Library of Science
Project: SFRH/BD/15229/2004 
POCTI/SAU-OBS/57772/2004 
PDTC/SAUOSM/ 67498/2006 
Serial title, monograph or event: PLoS ONE
Volume: 5
Issue: 11
Abstract: 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-1α under hypoxia. Significantly, MGO-induced degradation of HIF-1α did not require the recruitment of the ubiquitin ligase pVHL nor did it require hydroxylation of the proline residues P402/P564 of HIF-1α. Moreover, we identified CHIP (Carboxy terminus of Hsp70-Interacting Protein) as the E3 ligase that ubiquitinated HIF-1α in the presence of MGO. Consistently, silencing of endogenous CHIP and overexpression of glyoxalase I both stabilized HIF-1α under hypoxia in the presence of MGO. Data shows that increased association of Hsp40/70 with HIF-1α led to recruitment of CHIP, which promoted polyubiquitination and degradation of HIF-1α. Moreover, MGO-induced destabilization of HIF-1α led to a dramatic decrease in HIF-1 transcriptional activity. Altogether, data is consistent with a new pathway for degradation of HIF-1α 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.
URI: https://hdl.handle.net/10316/110213
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0015062
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
I&D IBILI - Artigos em Revistas Internacionais

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