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Functional interaction of heat shock protein 90 and Beclin 1 modulates Toll‐like receptor‐mediated autophagy
Author(s) -
Xu Congfeng,
Liu Jin,
Hsu LiChung,
Luo Yunping,
Xiang Rong,
Chuang TsungHsien
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-167676
Subject(s) - autophagy , hsp90 , microbiology and biotechnology , geldanamycin , heat shock protein , tlr4 , chemistry , receptor , effector , trif , biology , signal transduction , toll like receptor , innate immune system , apoptosis , biochemistry , gene
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.—Xu, C., Liu, J., Hsu, L. ‐C., Luo, Y., Xiang, R., Chuang, T. ‐H. Functional interaction of Hsp90 and Beclin 1 modulates Toll‐like receptor‐mediated autophagy. FASEB J. 25, 2700‐2710 (2011). www.fasebj.org