Shimizu Kei, Kiuchi Yukari, Ando Ken, Hayakawa Makio, Kikugawa Kiyomi
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Biochem Biophys Res Commun. 2004 Nov 5;324(1):140-6. doi: 10.1016/j.bbrc.2004.08.231.
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.
变性蛋白质在细胞内的积累会损害细胞功能。蛋白酶体被认为是一种负责有效清除那些具有细胞毒性的变性蛋白质的酶。作为另一种参与受损蛋白质破坏的酶，我们已经鉴定出氧化蛋白质水解酶（OPH），并发现OPH赋予细胞对各种氧化应激的抗性。在本研究中，我们证明了蛋白酶体和OPH在变性蛋白质清除中的作用。蛋白酶体活性的抑制导致氧化应激下细胞中蛋白质羰基含量升高。另一方面，即使蛋白酶体活性受到抑制，过表达OPH的细胞对氧化应激仍保持较高抗性。此外，在蛋白酶体活性受到抑制时，OPH会被募集到一种称为聚集体的新型细胞器中，在那里错误折叠或变性的蛋白质会被处理。因此，OPH和蛋白酶体协同作用于细胞毒性变性蛋白质的清除。
