title: Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells.
abstract: Argonaute proteins and small RNAs together form the RNA-induced silencing complex (RISC), the central effector of RNA interference (RNAi). The molecular chaperone Hsp90 is required for the critical step of loading small RNAs onto Argonaute proteins. Here we show that the Hsp90 cochaperones Cdc37, Aha1, FKBP4, and p23 are required for efficient RNAi. Whereas FKBP4 and p23 form a stable complex with hAgo2, the function of Cdc37 in RNAi appears to be indirect and may indicate that two or more Hsp90 complexes are involved. Our data also suggest that p23 and FKBP4 interact with hAgo2 before small RNA loading and that RISC loading takes place in the cytoplasm rather than in association with RNA granules. Given the requirement for p23 and FKBP4 for efficient RNAi and that these cochaperones bind to hAgo2, we predict that loading of hAgo2 is analogous to Hsp90-mediated steroid hormone receptor activation. To this end, we outline a model in which FKBP4, p23, and Aha1 cooperatively regulate the progression of hAgo2 through the chaperone cycle. Finally, we propose that hAgo2 and RNAi can serve as a robust model system for continued investigation into the Hsp90 chaperone cycle.
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada. jpare@ualberta.ca
authors.forename: Justin M
authors.initials: JM
authors.lastname: Pare
authors.forename: Paul
authors.initials: P
authors.lastname: LaPointe
authors.forename: Tom C
authors.initials: TC
authors.lastname: Hobman
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases