title: Porcine circovirus type 2 capsid protein induces unfolded protein response with subsequent activation of apoptosis.
abstract: Porcine circovirus type 2 (PCV2) has recently been reported to elicit the unfolded protein response (UPR) via activation of the PERK/eIF2α (RNA-activated protein kinase-like endoplasmic reticulum (ER) kinase/eukaryotic initiation factor 2α) pathway. This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein. By transient expression, we found that both replicase (Rep) and capsid (Cap) proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eIF2α-ATF4 (activating transcription factor 4)-CHOP (CCAAT/enhancer-binding protein homologous protein) axis. Cap expression, but not Rep, significantly reduced anti-apoptotic B-cell lymphoma-2 (Bcl-2) and increased caspase-3 cleavage, possibly due to increased expression of CHOP. Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression, caspase-3 cleavage, and apoptotic cell death possibly by partially rescuing Bcl-2 expression, we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eIF2α/ATF4/CHOP/Bcl-2 pathway. This study, together with our earlier studies, provides insight into the mechanisms underlying PCV2 pathogenesis.
authors.affiliation: College of Animal Science and Technology, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang A&F University, Lin'an 311300, China.
authors.forename: Ying-Shan
authors.initials: YS
authors.lastname: Zhou
authors.affiliation: Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yuan-Xing
authors.initials: YX
authors.lastname: Gu
authors.affiliation: Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Qi
authors.affiliation: Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yi-Kai
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Li
authors.affiliation: College of Animal Science and Technology, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang A&F University, Lin'an 311300, China.|Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Wei-Huan
authors.initials: WH
authors.lastname: Fang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D036022:Capsid Proteins / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D017925:Circovirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D036022:Capsid Proteins; D053148:Caspase 3; D019253:Proto-Oncogene Proteins c-bcl-2; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase
keywords: Porcine circovirus 2; Capsid protein; Unfolded protein response; Apoptosis