S6K1 negatively regulates TAK1 activity in the toll-like receptor signaling pathway

Mol Cell Biol. 2014 Feb;34(3):510-21. doi: 10.1128/MCB.01225-13. Epub 2013 Nov 25.


Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-κB and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1(-/-) and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1(-/-) mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-κB-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding / drug effects
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction*
  • Toll-Like Receptor 2 / agonists
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Lipopolysaccharides
  • NF-kappa B
  • TAB1 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7