title: Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1.
abstract: Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor alpha (TNFalpha)-induced nuclear factor kappaB (NF-kappaB) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNFalpha-induced RIP1 ubiquitination, IkappaB kinase beta (IKKbeta), and NF-kappaB phosphorylation, inhibitor of NF-kappaB alpha (IkappaB alpha) phosphorylation and ubiquitination, as well as NF-kappaB-dependent gene expression. Therefore, our results demonstrate that USP21 plays an important role in the down-regulation of TNFalpha-induced NF-kappaB activation through deubiquitinating RIP1.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Gufeng
authors.initials: G
authors.lastname: Xu
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Susan
authors.initials: S
authors.lastname: Burlingame
authors.forename: Xue
authors.initials: X
authors.lastname: Gu
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C408875:USP21 protein, human; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D051550:I-kappa B Kinase; D043222:Ubiquitin Thiolesterase