SH3 domain-mediated recruitment of host cell amphiphysins by alphavirus nsP3 promotes viral RNA replication
Autor(es): Neuvonen Maarit, Kazlauskas Arunas, Martikainen Miika, Hinkkanen Ari, Ahola Tero, Saksela Kalle
Resumo: Among the four non-structural proteins of alphaviruses the function of nsP3 is the least well understood. NsP3 is a component of the viral replication complex, - composed of a conserved aminoterminal macro domain implicated in viral RNA synthesis, - a poorly conserved carboxyterminal region. Despite the lack of overall homology we noted a carboxyterminal proline-rich sequence motif shared by many alphaviral nsP3 proteins, - found it to serve as a preferred target site for the Src-homology 3 (SH3) domains of amphiphysin-1 - -2. Nsp3 proteins of Semliki Forest (SFV), Sindbis (SINV), - Chikungunya viruses all showed avid - SH3-dependent binding to amphiphysins. Upon alphavirus infection the intracellular distribution of amphiphysin was dramatically altered - colocalized with nsP3. Mutations in nsP3 disrupting the amphiphysin SH3 binding motif as well as RNAi-mediated silencing of amphiphysin-2 expression resulted in impaired viral RNA replication in HeLa cells infected with SINV or SFV. Infection of Balb/c mice with SFV carrying an SH3 binding-defective nsP3 was associated with significantly decreased mortality. These data establish SH3 domain-mediated binding of nsP3 with amphiphysin as an important host cell interaction promoting alphavirus replication.
Imprenta: PLoS Pathogens, v. 7, n. 11, p. e1002383, 2011
Identificador do objeto digital: 10.1371/journal.ppat.1002383
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Molecular structure ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya Virus - Virus
Data de publicação: 2011
