FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly.
This study presents a molecular inhibitory mechanism by Fas-associated factor 1 (FAF1) on IkappaB kinase (IKK) activation, where divergent NF-kappaB-activating stimuli converge. FAF1 interacts with IKKbeta in response to proinflammatory stimuli (such as tumor necrosis factor-alpha, interleukin-1beta, and lipopolysaccharide) and suppresses IKK activation. Interaction of the leucine-zipper domain of IKKbeta with FAF1 affected the IKK heterocomplex (IKKalpha/beta) and homocomplex (IKKalpha/alpha, IKKbeta/beta) formations and attenuated IKKgamma recruitment to IKKbeta. Overexpression of FAF1 reduced the level of IKKbeta activity, whereas FAF1 depletion increased the activity. These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKbeta. Taken together, FAF1 robustly suppresses NF-kappaB activation through the inhibition of IKK activation in combination with previously reported cytoplasmic retention of NF-kappaB p65 (Park, M. Y., Jang, H. D., Lee, S. Y., Lee, K. J., and Kim, E. (2004) J. Biol. Chem. 279, 2544-2549). Such redundant suppression would prevent inadvertent activation of the NF-kappaB pathway.
Park
Min-Young
MY
Research Center for Biomedicinal Resources, PaiChai University, Daejeon 302-735, Korea.
Moon
Ji-hyun
JH
Lee
Ki-Sung
KS
Choi
Hye-In
HI
Chung
Jongkyeong
J
Hong
Hyo Jeong
HJ
Kim
Eunhee
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C490780:FAF1 protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D051550:I-kappa B Kinase