| First Author | Shim SM | Year | 2012 |
| Journal | Cell Rep | Volume | 2 |
| Issue | 3 | Pages | 603-15 |
| PubMed ID | 22921402 | Mgi Jnum | J:229228 |
| Mgi Id | MGI:5751062 | Doi | 10.1016/j.celrep.2012.07.013 |
| Citation | Shim SM, et al. (2012) Role of S5b/PSMD5 in proteasome inhibition caused by TNF-alpha/NFkappaB in higher eukaryotes. Cell Rep 2(3):603-15 |
| abstractText | 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 NFkappaB activation was selected as an inhibitor of 26S proteasome. TNF-alpha increased S5b (HGNC symbol PSMD5; hereafter S5b/PSMD5) expression via NFkappaB, and the surplus S5b/PSMD5 directly inhibited 26S proteasome assembly and activity. Downregulation of S5b/PSMD5 abolished TNF-alpha-induced proteasome inhibition. TNF-alpha enhanced the interaction of S5b/PSMD5 with S7/PSMC2 in nonproteasome complexes, and interference of this interaction rescued TNF-alpha-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-alpha/NFkappaB and provide insights into proteasome inhibition in human disease. |
