Similar articles

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.

猪圆环病毒2型衣壳蛋白通过未折叠蛋白反应诱导凋亡

[1]Ambrose, R.L., Mackenzie, J.M., 2011. West Nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion. J. Virol., 85(6): 2723-2732.

[2]Ambrose, R.L., Mackenzie, J.M., 2013. ATF6 signaling is required for efficient West Nile virus replication by promoting cell survival and inhibition of innate immune responses. J. Virol., 87(4):2206-2214.

[3]Benali-Furet, N.L., Chami, M., Houel, L., et al., 2005. Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene, 24(31):4921-4933.

[4]Chan, S.W., Egan, P.A., 2005. Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response. FASEB J., 19(11):1510-1512.

[5]Dey, S., Savant, S., Teske, B.F., et al., 2012. Transcriptional repression of ATF4 gene by CCAAT/enhancer-binding protein β (C/EBPβ) differentially regulates integrated stress response. J. Biol. Chem., 287(26):21936-21949.

[6]Finsterbusch, T., Mankertz, A., 2009. Porcine circoviruses— small but powerful. Virus Res., 143(2):177-183.

[7]Gilpin, D.F., McCullough, K., Meehan, B.M., et al., 2003. In vitro studies on the infection and replication of porcine circovirus type 2 in cells of the porcine immune system. Vet. Immunol. Immunopathol., 94(3-4):149-161.

[8]Gu, Y., Qi, B., Zhou, Y., et al., 2016. Porcine circovirus type 2 activates CaMMKβ to initiate autophagy in PK-15 cells by increasing cytosolic calcium. Viruses, 8(5):135.

[9]He, J., Cao, J., Zhou, N., et al., 2013. Identification and functional analysis of the novel ORF4 protein encoded by porcine circovirus type 2. J. Virol., 87(3):1420-1429.

[10]Hetz, C., 2012. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol., 13(2):89-102.

[11]Isler, J.A., Skalet, A.H., Alwine, J.C., 2005. Human cytomegalovirus infection activates and regulates the unfolded protein response. J. Virol., 79(11):6890-6899.

[12]Li, B., Gao, B., Ye, L., et al., 2007. Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. Virus Res., 124(1-2):44-49.

[13]Li, S., Kong, L., Yu, X., 2015. The expanding roles of endoplasmic reticulum stress in virus replication and pathogenesis. Crit. Rev. Microbiol., 41(2):150-164.

[14]Liao, Y., Fung, T.S., Huang, M., et al., 2013. Upregulation of CHOP/GADD153 during coronavirus infectious bronchitis virus infection modulates apoptosis by restricting activation of the extracellular signal-regulated kinase pathway. J. Virol., 87(14):8124-8134.

[15]Liu, J., Chen, I., Kwang, J., 2005. Characterization of a previously unidentified viral protein in porcine circovirus type 2-infected cells and its role in virus-induced apoptosis. J. Virol., 79(13):8262-8274.

[16]Liu, J., Chen, I., Du, Q., et al., 2006. The ORF3 protein of porcine circovirus type 2 is involved in viral pathogenesis in vivo. J. Virol., 80(10):5065-5073.

[17]Liu, Q., Tikoo, S.K., Babiuk, L.A., 2001. Nuclear localization of the ORF2 protein encoded by porcine circovirus type 2. Virology, 285(1):91-99.

[18]Lv, Q., Guo, K., Xu, H., et al., 2015. Identification of putative ORF5 protein of porcine circovirus type 2 and functional analysis of GFP-fused ORF5 protein. PLoS ONE, 10(6): e0127859.

[19]Mankertz, A., Mankertz, J., Wolf, K., et al., 1998. Identification of a protein essential for replication of porcine circovirus. J. Gen. Virol., 79(Pt 2):381-384.

[20]Meng, X.J., 2013. Porcine circovirus type 2 (PCV2): pathogenesis and interaction with the immune system. Annu. Rev. Anim. Biosci., 1(1):43-64.

[21]Moreno, J.A., Radford, H., Peretti, D., et al., 2012. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature, 485(7399):507-511.

[22]Nawagitgul, P., Morozov, I., Bolin, S.R., et al., 2000. Open reading frame 2 of porcine circovirus type 2 encodes a major capsid protein. J. Gen. Virol., 81(Pt 9):2281-2287.

[23]Oyadomari, S., Mori, M., 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ., 11(4): 381-389.

[24]Palam, L.R., Baird, T.D., Wek, R.C., 2011. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J. Biol. Chem., 286(13):10939-10949.

[25]Roberson, E.C., Tully, J.E., Guala, A.S., et al., 2012. Influenza induces endoplasmic reticulum stress, caspase-12-dependent apoptosis, and c-Jun N-terminal kinase-mediated transforming growth factor-β release in lung epithelial cells. Am. J. Resp. Cell Mol., 46(5):573-581.

[26]Su, H.L., Liao, C.L., Lin, Y.L., 2002. Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J. Virol., 76(9):4162-4171.

[27]Tabas, I., Ron, D., 2011. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol., 13(3):184-190.

[28]Timmusk, S., Fossum, C., Berg, M., 2006. Porcine circovirus type 2 replicase binds the capsid protein and an intermediate filament-like protein. J. Gen. Virol., 87(Pt 11):3215-3223.

[29]Walia, R., Dardari, R., Chaiyakul, M., et al., 2014. Porcine circovirus-2 capsid protein induces cell death in PK15 cells. Virology, 468-470:126-132.

[30]Zhou, Y., Qi, B., Gu, Y., et al., 2016. Porcine circovirus 2 deploys PERK pathway and GRP78 for its enhanced replication in PK-15 cells. Viruses, 8(2):56.

[31]Zhu, B., Xu, F., Li, J., et al., 2012a. Porcine circovirus type 2 explores the autophagic machinery for replication in PK-15 cells. Virus Res., 163(2):476-485.

[32]Zhu, B., Zhou, Y., Xu, F., et al., 2012b. Porcine circovirus type 2 induces autophagy via the AMPK/ERK/TSC2/mTOR signaling pathway in PK-15 cells. J. Virol., 86(22): 12003-12012.