Salt-inducible kinases 1 and 3 negatively regulate Toll-like receptor 4-mediated signal

Mol Endocrinol. 2013 Nov;27(11):1958-68. doi: 10.1210/me.2013-1240. Epub 2013 Sep 23.


Salt-inducible kinases (SIKs) are a family of related serine-threonine kinases and are involved in controlling various metabolisms such as liver glucose homeostasis, hepatic lipogenesis, steroidogenesis, and adipogenesis. Here we investigated the regulatory role of SIK proteins in Toll-like receptor 4 (TLR4)-mediated signaling. Overexpression of SIK1 and SIK3, but not SIK2, significantly inhibited nuclear factor-κB activity in response to lipopolysaccharide stimulation and affected the expression of proinflammatory cytokines. In contrast, both SIK1(KD) and SIK3(KD) Raw 264.7 cells exhibit dramatic elevations of nuclear factor-κB activation and activations of downstream signaling molecules, such as TGF-β-activated kinase 1, p38, and c-Jun N-terminal kinase, in response to TLR4 stimulation, indicating that SIK1 and SIK3 are negatively involved in the TLR4-mediated signaling. Through biochemical studies, we found that SIK1 and SIK3 interact with TGF-β-activated kinase 1-binding protein 2 (TAB2), and interrupt the functional complex of TAB2-TNF receptor-associated factor 6 (TRAF6). Interestingly, the molecular interruption is induced to suppress the ubiquitination of TRAF6 in response to TLR4 stimulation. These result suggest that SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6. The present findings can be useful for a better understanding of multilevel interactions between the metabolic and immune systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / enzymology
  • Macrophages / immunology
  • Mice
  • NF-kappa B / metabolism
  • Protein Serine-Threonine Kinases / physiology*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptor 4 / metabolism*
  • Transcriptional Activation
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Tab2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Protein Serine-Threonine Kinases
  • SIK3 protein, mouse
  • Sik1 protein, mouse

Grant support

This work was supported by a grant from the Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, Republic of Korea (Grant A111636).