title: USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha.
abstract: IkappaBalpha serves as a central anchoring molecule in the sequestration of NF-kappaB transcription factor in the cytoplasm. Ubiquitination-mediated IkappaBalpha degradation immediately precedes and is required for NF-kappaB nuclear translocation and activation. However, the precise mechanism for the deubiquitination of IkappaBalpha is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Peptidase 11 (USP11) as an IkappaBalpha associated deubiquitinase. Overexpression of USP11 inhibits IkappaBalpha ubiquitination. Recombinant USP11 catalyzes deubiquitination of IkappaBalpha in vitro. Moreover, knockdown of USP11 expression enhances TNFalpha-induced IkappaBalpha ubiquitination and NF-kappaB activation. These data demonstrate that USP11 plays an important role in the downregulation of TNFalpha-mediated NF-kappaB activation through modulating IkappaBalpha stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNFalpha- and IKKbeta-induced NF-kappaB activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNFalpha-mediated NF-kappaB activation. Thus, IkappaBalpha ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNFalpha-induced NF-kappaB activation.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Gufeng
authors.initials: G
authors.lastname: Xu
authors.forename: Renfang
authors.initials: R
authors.lastname: Mao
authors.forename: Xue
authors.initials: X
authors.lastname: Gu
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Susan
authors.initials: S
authors.lastname: Burlingame
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Surya P
authors.initials: SP
authors.lastname: Rednam
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination; D016709:Yin-Yang
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C101359:USP11 protein, human; D051550:I-kappa B Kinase; D013869:Thiolester Hydrolases