Zhang Yuanyuan, Liu Shuang, Zuo Qiuhong, Wu Lin, Ji Lei, Zhai Wanli, Xiao Jianru, Chen Jiwu, Li Xiaotao
Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China; Department of Hematology, Guangdong No. 2 People Provincial Hospital, No. 1, Shiliugang Rd, Guangzhou, Guangdong, 510317, China.
Free Radic Biol Med. 2015 May;82:42-9. doi: 10.1016/j.freeradbiomed.2015.01.024. Epub 2015 Feb 2.
Elimination of oxidized proteins is important to cells as accumulation of damaged proteins causes cellular dysfunction, disease, and aging. Abundant evidence shows that the 20S proteasome is largely responsible for degradation of oxidative proteins in both ubiquitin-dependent and ubiquitin-independent pathways. However, the role of the REGγ-proteasome in degrading oxidative proteins remains unclear. Here, we focus on two of the well-known REGγ-proteasome substrates, p21(Waf1/Cip1) and hepatitis C virus (HCV) core protein, to analyze the impact of oxidative stress on REGγ-proteasome functions. We demonstrate that REGγ-proteasome is essential for oxidative stress-induced rapid degradation of p21 and HCV proteins. Silencing REGγ abrogated this response in multiple cell lines. Furthermore, pretreatment with proteasome inhibitor MG132 completely blunted oxidant-induced p21 degradation, indicating a proteasome-dependent action. Cellular oxidation promoted REGγ-proteasome-dependent trypsin-like activity by enhancing the interaction between REGγ and 20S proteasome. Antioxidant could counteract oxidation-induced protein degradation, indicating that REGγ-proteasome activity may be regulated by redox state. This study provides further insights into the actions of a unique proteasome pathway in response to an oxidative stress environment, implying a novel molecular basis for REGγ-proteasome functions in antioxidation.
清除氧化蛋白对细胞至关重要，因为受损蛋白的积累会导致细胞功能障碍、疾病和衰老。大量证据表明，20S蛋白酶体在泛素依赖性和泛素非依赖性途径中很大程度上负责氧化蛋白的降解。然而，REGγ-蛋白酶体在降解氧化蛋白中的作用仍不清楚。在此，我们聚焦于两个著名的REGγ-蛋白酶体底物，p21（Waf1/Cip1）和丙型肝炎病毒（HCV）核心蛋白，以分析氧化应激对REGγ-蛋白酶体功能的影响。我们证明REGγ-蛋白酶体对于氧化应激诱导的p21和HCV蛋白的快速降解至关重要。在多种细胞系中沉默REGγ可消除这种反应。此外，用蛋白酶体抑制剂MG132预处理完全抑制了氧化剂诱导的p21降解，表明这是一种蛋白酶体依赖性作用。细胞氧化通过增强REGγ与20S蛋白酶体之间的相互作用促进了REGγ-蛋白酶体依赖性胰蛋白酶样活性。抗氧化剂可以抵消氧化诱导的蛋白质降解，表明REGγ-蛋白酶体活性可能受氧化还原状态调节。本研究进一步深入了解了独特蛋白酶体途径在应对氧化应激环境中的作用，暗示了REGγ-蛋白酶体在抗氧化中的新分子基础。
