Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
Cell Rep. 2012 Sep 27;2(3):603-15. doi: 10.1016/j.celrep.2012.07.013. Epub 2012 Aug 23.
The ubiquitin-proteasome system is essential for maintaining protein homeostasis. However, proteasome dysregulation in chronic diseases is poorly understood. Through genome-wide cell-based screening using 5,500 cDNAs, a signaling pathway leading to NFκB activation was selected as an inhibitor of 26S proteasome. TNF-α increased S5b (HGNC symbol PSMD5; hereafter S5b/PSMD5) expression via NFκB, and the surplus S5b/PSMD5 directly inhibited 26S proteasome assembly and activity. Downregulation of S5b/PSMD5 abolished TNF-α-induced proteasome inhibition. TNF-α enhanced the interaction of S5b/PSMD5 with S7/PSMC2 in nonproteasome complexes, and interference of this interaction rescued TNF-α-induced proteasome inhibition. Transgenic mice expressing S5b/PSMD5 exhibited a reduced life span and premature onset of aging-related phenotypes, including reduced proteasome activity in their tissues. Conversely, S5b/PSMD5 deficiency in Drosophila melanogaster ameliorated the tau rough eye phenotype, enhanced proteasome activity, and extended the life span of tau flies. These results reveal the critical role of S5b/PSMD5 in negative regulation of proteasome by TNF-α/NFκB and provide insights into proteasome inhibition in human disease.
泛素-蛋白酶体系统对于维持蛋白质的内稳态至关重要。然而，慢性疾病中蛋白酶体的失调机制仍知之甚少。通过使用 5500 个 cDNA 进行全基因组细胞筛选，选择了一条导致 NFκB 激活的信号通路，作为 26S 蛋白酶体的抑制剂。TNF-α 通过 NFκB 增加 S5b（HGNC 符号 PSMD5；以下简称 S5b/PSMD5）的表达，多余的 S5b/PSMD5 直接抑制 26S 蛋白酶体的组装和活性。下调 S5b/PSMD5 可消除 TNF-α 诱导的蛋白酶体抑制。TNF-α 增强了 S5b/PSMD5 与非蛋白酶体复合物中 S7/PSMC2 的相互作用，干扰这种相互作用可挽救 TNF-α 诱导的蛋白酶体抑制。表达 S5b/PSMD5 的转基因小鼠表现出寿命缩短和与衰老相关表型的提前出现，包括其组织中蛋白酶体活性降低。相反，果蝇中 S5b/PSMD5 的缺失改善了 tau 粗糙眼表型，增强了蛋白酶体活性，并延长了 tau 果蝇的寿命。这些结果揭示了 S5b/PSMD5 在 TNF-α/NFκB 负调控蛋白酶体中的关键作用，并为人类疾病中的蛋白酶体抑制提供了新的见解。
