Functional interaction of heat shock protein 90 and Beclin 1 modulates Toll-like receptor-mediated autophagy.

Autophagy is one of the downstream effector mechanisms for elimination of intracellular microbes following activation of the Toll-like receptors (TLRs). Although the detailed molecular mechanism for this cellular process is still unclear, Beclin 1, a key molecule for autophagy, has been suggested to play a role. Heat shock protein 90 ...
(Hsp90) is a molecular chaperone that regulates the stability of signaling proteins. Herein, we show that Hsp90 forms a complex with Beclin 1 through an evolutionarily conserved domain to maintain the stability of Beclin 1. In monocytic cells, geldanamycin (GA), an Hsp90 inhibitor, effectively promoted proteasomal degradation of Beclin 1 in a concentration-dependent (EC(50) 100 nM) and time-dependent (t(50) 2 h) manner. In contrast, KNK437/Hsp inhibitor I had no effect. Hsp90 specifically interacted with Beclin 1 but not with other adapter proteins in the TLR signalsome. Treatment of cells with GA inhibited TLR3- and TLR4-mediated autophagy. In addition, S. typhimurium infection-induced autophagy was blocked by GA treatment. This further suggested a role of the Hsp90/Beclin 1 in controlling autophagy in response to microbial infections. Taken together, our data revealed that by maintaining the homeostasis of Beclin 1, Hsp90 plays a novel role in TLR-mediated autophagy.
Mesh Terms:
Animals, Apoptosis Regulatory Proteins, Autophagy, Benzoquinones, Cell Line, Evolution, Molecular, HEK293 Cells, HSP90 Heat-Shock Proteins, Humans, Immunity, Innate, Interferon-beta, Lactams, Macrocyclic, Membrane Proteins, Mice, Models, Biological, Multiprotein Complexes, NF-kappa B, Protein Interaction Domains and Motifs, Signal Transduction, Toll-Like Receptor 3, Toll-Like Receptor 4, Toll-Like Receptors, Ubiquitination
FASEB J.
Date: Aug. 01, 2011
Download Curated Data For This Publication
127828
Switch View:
  • Interactions 4
  • PTM Genes 1