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

Dong Joo You, Cho Rong Park, Michael Furlong, Okjae Koo, Cheolju Lee, Curie Ahn, Jae Young Seong, Jong Ik Hwang

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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 upstream signals 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-specific manner. In this study, arfaptin 2 was identified as an IKKβ-specific binding partner. Interestingly, arfaptin 2 also interacted with NEMO. Domain mapping studies revealed that the C-terminal region, including the IKKβ HLH domain and the first coiled-coil NEMO 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 interfering RNA enhanced NF-κB activity. Dimerization of arfaptin 2 through the Bin-Amphiphysin-Rvs domain may be essential to inhibit activation of NF-κB through multimodal interactions with 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.

Original languageEnglish
Pages (from-to)2173-2181
Number of pages9
JournalCellular Signalling
Issue number11
Publication statusPublished - 2015 Nov 1

Bibliographical note

Funding Information:
This study was supported by the Korea Research Foundation Grant to J.-I. H. funded by the Korean Government ( Ministry of Science, ICT, and Future Planning : MSIP) (no. NRF-2013R1A1A2005949 ).

Publisher Copyright:
© 2015 Elsevier Inc.


  • Arfaptin 2
  • BAR domain
  • IκB kinases
  • NF-κB
  • TNF-α

ASJC Scopus subject areas

  • Cell Biology


Dive into the research topics of 'Dimer of arfaptin 2 regulates NF-κB signaling by interacting with IKKβ/NEMO and inhibiting IKKβ kinase activity'. Together they form a unique fingerprint.

Cite this