Article ID Journal Published Year Pages File Type
2832327 Molecular Immunology 2009 10 Pages PDF
Abstract

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 β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK), and is essential in interleukin-1β (IL-1β) triggered signaling pathways. In the present study, we found that Hsp90 plays an important role in regulating IL-1β signaling by keeping TAK1 stability. The results showed that the specific inhibitor geldanamycin (GA) of Hsp90 dramatically inhibited IL-1β stimulated TAK1-MAPKs and TAK1-nuclear factor-κB (NF-κB) 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-1β induced phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 MAPKs, and degradation of IκBα. The same results were obtained in T6RZC stable cells which initiated IL-1β-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-1β-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.

Related Topics
Life Sciences Biochemistry, Genetics and Molecular Biology Molecular Biology
Authors
, , , , , , , , ,