title: Functional interaction of heat shock protein 90 and Beclin 1 modulates Toll-like receptor-mediated autophagy.
abstract: 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.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Congfeng
authors.initials: C
authors.lastname: Xu
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Hsu
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D000071186:Beclin-1; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D019143:Evolution, Molecular; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016899:Interferon-beta; C001277:geldanamycin