Chikungunya virus non-structural protein 2-mediated host shut-off disables the unfolded protein response
Autor(es): Fros Jelke J, Major Lee D, Scholte Florine E M, Gardner Joy, van Hemert Martijn J, Suhrbier Andreas, Pijlman Gorben P
Resumo: The unfolded protein response (UPR) is a cellular defence mechanism against high concentrations of misfolded protein in the endoplasmic reticulum (ER). In the presence of misfolded proteins, ER-transmembrane proteins PERK - IRE1? become activated. PERK phosphorylates eIF2? leading to a general inhibition of cellular translation, whilst the expression of transcription factor ATF4 is upregulated. Active IRE1? splices out an intron from XBP1 mRNA, to produce a potent transcription factor. Activation of the UPR increases the production of several proteins involved in protein folding, degradation - apoptosis. Here, we demonstrated that transient expression of chikungunya virus (CHIKV) (family Togaviridae, genus Alphavirus) envelope glycoproteins induced the UPR - that CHIKV infection resulted in the phosphorylation of eIF2? - partial splicing of XBP1 mRNA. However, infection with CHIKV did not increase the expression of ATF4 - known UPR target genes (GRP78/BiP, GRP94 - CHOP). Moreover, nuclear XBP1 was not observed during CHIKV infection. Even upon stimulation with tunicamycin, the UPR was efficiently inhibited in CHIKV-infected cells. Individual expression of CHIKV non-structural proteins (nsPs) revealed that nsP2 alone was sufficient to inhibit the UPR. Mutations that rendered nsP2 unable to cause host-cell shut-off prevented nsP2-mediated inhibition of the UPR. This indicates that initial UPR induction takes place in the ER but that expression of functional UPR transcription factors - target genes is efficiently inhibited by CHIKV nsP2.
Imprenta: The Journal of General Virology, v. 96, Pt 3, p. 580-589, 2015
Identificador do objeto digital: 10.1099/vir.0.071845-0
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - DNA ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Molecular screening ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Immunology
Data de publicação: 2015
