USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha.
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.
Sun
Wenjing
W
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
Tan
Xiaojie
X
Shi
Yi
Y
Xu
Gufeng
G
Mao
Renfang
R
Gu
Xue
X
Fan
Yihui
Y
Yu
Yang
Y
Burlingame
Susan
S
Zhang
Hong
H
Rednam
Surya P
SP
Lu
Xiongbin
X
Zhang
Ting
T
Fu
Songbin
S
Cao
Guangwen
G
Qin
Jun
J
Yang
Jianhua
J
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
D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C101359:USP11 protein, human; D051550:I-kappa B Kinase; D013869:Thiolester Hydrolases