Coordination of oxidized protein hydrolase and the proteasome in the clearance of cytotoxic denatured proteins.
Intracellular accumulation of denatured proteins impairs cellular function. The proteasome is recognized as an enzyme responsible for the effective clearance of those cytotoxic denatured proteins. As another enzyme that participates in the destruction of damaged proteins, we have identified oxidized protein hydrolase (OPH) and found that OPH confers cellular resistance to various kinds of oxidative stress. In this study, we demonstrate the roles of the proteasome and OPH in the clearance of denatured proteins. The inhibition of proteasome activity results in the elevation of protein carbonyls in cells under oxidative stress. On the other hand, cells overexpressing OPH retain higher resistance to oxidative stress, even though the proteasome activity is inhibited. Furthermore, upon inhibition of the proteasome activity, OPH is recruited to a novel organelle termed the aggresome where misfolded or denatured proteins are processed. Thus, OPH and the proteasome coordinately contribute to the clearance of cytotoxic denatured proteins.
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Kei
K
Shimizu
Yukari
Y
Kiuchi
Ken
K
Ando
Makio
M
Hayakawa
Kiyomi
K
Kikugawa
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010269:Paraquat / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011489:Protein Denaturation; D014404:Tubulin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D018840:HSP70 Heat-Shock Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D014404:Tubulin; D014746:Vimentin; C121811:acetylleucine chloromethyl ketone; C067713:lactacystin; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D046988:Proteasome Endopeptidase Complex; D010269:Paraquat; D000111:Acetylcysteine; C078846:epoxomicin