Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2α phosphorylation.
Chikungunya (CHIKV) and Sindbis (SINV) are arboviruses belonging to the alphavirus genus within the Togaviridae family. They cause frequent epidemics of febrile illness and long-term arthralgic sequelae that affect millions of people each year. Both viruses replicate prodigiously in infected patients and in vitro in mammalian cells, suggesting some level of control over the host cellular translational machinery that senses and appropriately directs the cell's fate through the unfolded protein response (UPR). The mammalian UPR involves BIP (or GRP78), the master sensor in the endoplasmic reticulum (ER) together with the three downstream effector branches: inositol-requiring ser/thr protein kinase/endonuclease (IRE-1), PKR-like ER resident kinase (PERK) and activating transcription factor 6 (ATF-6). Through careful analysis of CHIKV and SINV infections in cell culture we found that the former selectively activates ATF-6 and IRE-1 branches of UPR and suppresses the PERK pathway. By separately expressing each of the CHIKV proteins as GFP-fusion proteins, we found that non-structural protein 4 (nsP4), which is a RNA-dependent-RNA polymerase, suppresses the serine-51 phosphorylation of eukaryotic translation initiation factor, alpha subunit (eIF2α), which in turn regulates the PERK pathway. This study provides insight into a mechanism by which CHIKV replication responds to overcome the host UPR machinery.
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8-College Road, Singapore 169857, Singapore.
Abhay P S
AP
Rathore
Mah-Lee
ML
Ng
Subhash G
SG
Vasudevan
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002646:Chikungunya virus / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction; D012845:Sindbis Virus / Q000502:physiology*; D056811:Unfolded Protein Response; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human