title: Role of S5b/PSMD5 in proteasome inhibition caused by TNF-α/NFκB in higher eukaryotes.
abstract: 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.
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shim
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Youngdoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Chang
authors.forename: Sungmin
authors.initials: S
authors.lastname: Song
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D004331:Drosophila melanogaster; D006801:Humans; D008136:Longevity / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C075363:PSMC2 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000074183:ATPases Associated with Diverse Cellular Activities