the chaperone-dependent ubiquitin ligase chip targets hif-1α for degradation in the presence of methylglyoxalchaperone-dependent的泛素连接酶芯片目标hif-1α降解甲基乙二醛的存在.pdf

The Chaperone-Dependent Ubiquitin Ligase CHIP Targets HIF-1a for Degradation in the Presence of Methylglyoxal 1,2 1 ´ 1 1 3 3 Carla Figueira Bento , Rosa Fernandes , Jose Ramalho , Carla Marques , Fu Shang , Allen Taylor , Paulo Pereira1* 1 Center of Ophthalmology and Vision Sciences (COCV), Institute for Biomedical Research in Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal, 2 Experimental Biology and Biomedicine (BEB) PhD Programme, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal, 3 Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States of America 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-1a under hypoxia. Significantly, MGO- induced degradation of HIF-1a did not require the recruitment of the ubiquitin ligase pVHL nor did it require hydroxylation of the proline residues P402/P564 of HIF-1a. Moreover, we identified CHIP (Carboxy terminus of Hsp70-Interacting Protein) as the E3 ligase that u