Heat shock protein 90 (Hsp90) regulates the stability of transforming growth factor beta-activated kinase 1 (TAK1) in interleukin-1beta-induced cell signaling

Mol Immunol. 2009 Feb;46(4):541-50. doi: 10.1016/j.molimm.2008.07.019. Epub 2008 Oct 31.


Heat shock protein 90 (Hsp90) is an abundantly and ubiquitously expressed chaperone with majority of client proteins which act as signal molecules. Transforming growth factor beta-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK), and is essential in interleukin-1beta (IL-1beta) triggered signaling pathways. In the present study, we found that Hsp90 plays an important role in regulating IL-1beta signaling by keeping TAK1 stability. The results showed that the specific inhibitor geldanamycin (GA) of Hsp90 dramatically inhibited IL-1beta stimulated TAK1-MAPKs and TAK1-nuclear factor-kappaB (NF-kappaB) activation, resulting in the decrease of cyclooxygenase-2 (COX-2) protein expression. Silencing Hsp90 expression through RNA interference (RNAi) also down-regulated TAK1, as well as attenuated IL-1beta induced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 MAPKs, and degradation of IkappaBalpha. The same results were obtained in T6RZC stable cells which initiated IL-1beta-induced cell signaling at the level of the oligomerization and ubquitination of TNF receptor-associated factor 6 (TRAF6). We further found that Hsp90 formed a complex with TAK1 via its N-terminal domain and GA destabilized TAK1 and induced TAK1 degradation through proteasome pathway. Taken together our results demonstrate that Hsp90 regulates IL-1beta-induced signaling by interacting with TAK1 and maintaining the stability of TAK1, suggesting that Hsp90 might act as the chaperone of TAK1 in immune and inflammatory responses related with IL-1 signal cascades.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoquinones / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cyclooxygenase 2 / immunology
  • Cyclooxygenase 2 / metabolism*
  • Enzyme Inhibitors / pharmacology
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / immunology
  • HSP90 Heat-Shock Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lactams, Macrocyclic / pharmacology
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / immunology
  • MAP Kinase Kinase Kinases / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • RNA Interference
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 6 / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Benzoquinones
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • Interleukin-1beta
  • Lactams, Macrocyclic
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Proteasome Endopeptidase Complex
  • geldanamycin