Chikungunya virus non-structural protein 2-mediated host shut-off disables the unfolded protein response.
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 and IRE1α become activated. PERK phosphorylates eIF2α leading to a general inhibition of cellular translation, whilst the expression of transcription factor ATF4 is upregulated. Active IRE1α 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 and apoptosis. Here, we demonstrated that transient expression of chikungunya virus (CHIKV) (family Togaviridae, genus Alphavirus) envelope glycoproteins induced the UPR and that CHIKV infection resulted in the phosphorylation of eIF2α and partial splicing of XBP1 mRNA. However, infection with CHIKV did not increase the expression of ATF4 and known UPR target genes (GRP78/BiP, GRP94 and 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 and target genes is efficiently inhibited by CHIKV nsP2.
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.|Laboratory of Virology, Wageningen University, 6708 PB Wageningen, The Netherlands.
Jelke J
JJ
Fros
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
Lee D
LD
Major
Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Florine E M
FEM
Scholte
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
Joy
J
Gardner
Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Martijn J
MJ
van Hemert
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
Andreas
A
Suhrbier
Laboratory of Virology, Wageningen University, 6708 PB Wageningen, The Netherlands.
Gorben P
GP
Pijlman
D000818:Animals; D001170:Arthritis, Infectious; D065632:Chikungunya Fever / Q000473:pathology / Q000821:virology*; D002646:Chikungunya virus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology*; D051379:Mice; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000502:physiology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D014415:Tunicamycin