title: CHIP has a protective role against oxidative stress-induced cell death through specific regulation of endonuclease G.
abstract: Oxidative stress is implicated in carcinogenesis, aging, and neurodegenerative diseases. The E3 ligase C terminus of Hsc-70 interacting protein (CHIP) has a protective role against various stresses by targeting damaged proteins for proteasomal degradation, and thus maintains protein quality control. However, the detailed mechanism by which CHIP protects cells from oxidative stress has not been demonstrated. Here, we show that depletion of CHIP led to elevated Endonuclease G (EndoG) levels and enhanced cell death upon oxidative stress. In contrast, CHIP overexpression reduced EndoG levels, and resulted in reduced or no oxidative stress-induced cell death in cancer cells and primary rat cortical neurons. Under normal conditions Hsp70 mediated the interaction between EndoG and CHIP, downregulating EndoG levels in a Hsp70/proteasome-dependent manner. However, under oxidative stress Hsp70 no longer interacted with EndoG, and the stabilized EndoG translocated to the nucleus and degraded chromosomal DNA. Our data suggest that regulation of the level of EndoG by CHIP in normal conditions may determine the sensitivity to cell death upon oxidative stress. Indeed, injection of H2O2 into the rat brain markedly increased cell death in aged mice compared with young mice, which correlated with elevated levels of EndoG and concurrent downregulation of CHIP in aged mice. Taken together, our findings demonstrate a novel protective mechanism of CHIP against oxidative stress through regulation of EndoG, and provide an opportunity to modulate oxidative stress-induced cell death in cancer and aging.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: T W
authors.initials: TW
authors.lastname: Seo
authors.forename: J H
authors.initials: JH
authors.lastname: Yi
authors.forename: K S
authors.initials: KS
authors.lastname: Shin
authors.forename: S J
authors.initials: SJ
authors.lastname: Yoo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000201:enzymology; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D006861:Hydrogen Peroxide; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D046988:Proteasome Endopeptidase Complex