Heat shock protein 90 positively regulates Chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection
Autor(es): Das Indrani, Basantray Itishree, Mamidi Prabhudutta, Nayak Tapas K, B M Pratheek, Chattopadhyay Subhasis, Chattopadhyay Soma
Resumo: The high morbidity - socio-economic loss associated with the recent massive global outbreak of Chikungunya virus (CHIKV) emphasize the need to underst- the biology of the virus for developing effective antiviral therapies. In this study, an attempt was made to underst- the molecular mechanism involved in Heat shock protein 90 (Hsp90) mediated regulation of CHIKV infection in mammalian cells using CHIKV prototype strain (S 27) - Indian outbreak strain of 2006 (DRDE-06). Our results showed that Hsp90 is required at a very early stage of viral replication - Hsp90 inhibitor Geldanamycin (GA) can abrogate new virus particle formation more effectively in the case of S 27 than that of DRDE-06. Further analysis revealed that CHIKV nsP2 protein level is specifically reduced by GA treatment as well as HSP90-siRNA transfection; however, viral RNA remains unaltered. Immunoprecipitation analysis showed that nsP2 interacts with Hsp90 during infection; however this interaction is reduced in the presence of GA. In addition, our analysis on Hsp90 associated PI3K/Akt/mTOR signaling pathway demonstrated that CHIKV infection stabilizes Raf1 - activates Hsp90 client protein Akt, which in turn phosphorylates mTOR. Subsequently, this phosphorylation leads to the activation of two important downstream effectors, S6K - 4EBP1, which may facilitate translation of viral as well as cellular mRNAs. Hence, the data suggests that CHIKV infection is regulated by Hsp90 associated Akt phosphorylation - DRDE-06 is more efficient than S 27 in enhancing the activation of host signaling molecules for its efficient replication - virus production. Hsp90 positively regulates Chikungunya virus replication by stabilizing CHIKV-nsP2 through its interaction during infection. The study highlights the possible molecular mechanism of GA mediated inhibition of CHIKV replication - differential effect of this drug on S 27 - DRDE-06, which will be informative for developing effective anti-CHIKV therapies in future.
Imprenta: PloS One, v. 9, n. 6, p. e100531, 2014
Identificador do objeto digital: 10.1371/journal.pone.0100531
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Molecular methods ; Chikungunya Virus - Virus
Data de publicação: 2014
