Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKKβ

Biochim Biophys Acta. 2014 Jul;1843(7):1365-72. doi: 10.1016/j.bbamcr.2014.03.028. Epub 2014 Apr 12.

Abstract

Stringent negative regulation of the transcription factor NF-κB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKβ are still not clear. Here, we reported that nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFα)-induced NF-κB signaling by inhibiting the phosphorylation of IKKβ. Overexpression of NLK largely blocked TNFα-induced NF-κB activation, p65 nuclear localization and IκBα degradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IκB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKβ and thereby, diminished the IκB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFα-induced activation of NF-κB via disrupting the interaction of TAK1 with IKKβ.

Keywords: IKKβ; NF-κB; NLK; TAK1; TNFα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Gene Expression Regulation
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteolysis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • NLK protein, human
  • Protein Serine-Threonine Kinases
  • I-kappa B Kinase
  • IKBKB protein, human
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7