title: The co-chaperone Cdc37 regulates the rabies virus phosphoprotein stability by targeting to Hsp90AA1 machinery.
abstract: Cdc37, as a kinase-specific co-chaperone of the chaperone Hsp90AA1 (Hsp90), actively aids with the maturation, stabilization and activation of the cellular or viral kinase/kinase-like targets. Phosphoprotein (P) of rabies virus (RABV) is a multifunctional, non-kinase protein involved in interferon antagonism, viral transcription and replication. Here, we demonstrated that the RABV non-kinase P is chaperoned by Cdc37 and Hsp90 during infection. We found that Cdc37 and Hsp90 affect the RABV life cycle directly. Activity inhibition and knockdown of Cdc37 and Hsp90 increased the instability of the viral P protein. Overexpression of Cdc37 and Hsp90 maintained P's stability but did not increase the yield of infectious RABV virions. We further demonstrated that the non-enzymatic polymerase cofactor P protein of all the genotypes of lyssaviruses is a target of the Cdc37/Hsp90 complex. Cdc37, phosphorylated or unphosphorylated on Ser13, aids the P protein to load onto the Hsp90 machinery, with or without Cdc37 binding to Hsp90. However, the interaction between Cdc37 and Hsp90 appears to have additional allosteric regulation of the conformational switch of Hsp90. Our study highlighted a novel mechanism in which Cdc37/Hsp90 chaperones a non-kinase target, which has significant implications for designing therapeutic targets against Rabies.
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.|Collaborative Innovation Center and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, P. R. China.
authors.forename: Yunbin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.|Collaborative Innovation Center and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.|Collaborative Innovation Center and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Ji
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.|Collaborative Innovation Center and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zan
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou 310058, P. R. China.|Collaborative Innovation Center and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, P. R. China.|College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D011818:Rabies / Q000378:metabolism / Q000821:virology; D011820:Rabies virus / Q000378:metabolism / Q000472:pathogenicity*; D015678:Viral Structural Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C103961:P phosphoprotein, Rabies virus; D010750:Phosphoproteins; D015678:Viral Structural Proteins