Dimer of arfaptin 2 regulates NF-κB signaling by interacting with IKKβ/ NEMO and inhibiting IKKβkinase activity

Title
Dimer of arfaptin 2 regulates NF-κB signaling by interacting with IKKβ/ NEMO and inhibiting IKKβkinase activity
Authors
유동주박초롱Michael Furlong구옥재이철주안규리성재영황종익
Keywords
IκB kinases; Arfaptin 2; NF-κB; TNF-α; BAR domain
Issue Date
2015-11
Publisher
Cellular signalling
Citation
VOL 27, NO 11, 2173-2181
Abstract
IκB kinases (IKKs) are a therapeutic target due to their crucial roles in various biological processes, including the immune response, the stress response, and tumor development. IKKs integrate various upstreamsignals that activate NF-κB by phosphorylating IκB and also regulate many proteins related to cell growth and metabolism. Although they function as a heteromeric complex comprised of kinase subunits and an adaptor, these kinases produce distinct cellular responses by phosphorylating different target molecules, suggesting that they may also be regulated in a subtype-specificmanner. In this study, arfaptin 2was identified as an IKKβ-specific binding partner. Interestingly, arfaptin 2 also interacted with NEMO. Domain mapping studies revealed that the Cterminal region, including the IKKβHLHdomain and the first coiled-coilNEMO region were respectively required for interactions with the arfaptin 2 N-terminal flexible region. Overexpression of arfaptin 2 inhibited tumor necrosis factor (TNF)-α-stimulated nuclear factor-κB (NF-κB) signaling, whereas downregulation of arfaptin 2 by small interferingRNA enhancedNF-κB activity. Dimerization of arfaptin 2 through the Bin–Amphiphysin–Rvs domain may be essential to inhibit activation of NF-κB through multimodal interactionswith IKKβs or IKKβ/NEMO, as ectopic expression of the arfaptin 2 fragment responsible for IKK interactions did not change TNFα-stimulated NF-κB activation. These data indicate that arfaptin 2 is the first molecule to regulate NF-κB signaling by interacting with the functional IKK complex but not by direct inhibiting IKKβ phosphorylation.
URI
http://pubs.kist.re.kr/handle/201004/50537
ISSN
08986568
Appears in Collections:
KIST Publication > Article
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