Abstract
Bovine viral diarrhea virus (BVDV) is an important pathogen in cattle that causes economic losses in livestock industries. Autophagy is an essential cell system for the maintenance of homeostasis and is induced by various triggers, including infection by viruses. BVDV infection leads to autophagy in order to enhance its replication in cells. In this study, we investigated the effect of BVDV non-structural proteins on the induction of autophagosomes. We found that NS4B alone could induce autophagosomes, suggesting a novel and important function of NS4B in BVDV replication.
References
Baker JC (1995) The clinical manifestation of bovine viral diarrhea infection. Vet Clin N Am Food Anim Pract 11:425–445
Brodersen BW (2014) Bovine viral diarrhea virus infections: manifestations of infection and recent advances in understanding pathogenesis and control. Vet Pathol 51:453–464
Behrens SE, Grassmann CW, Thiel HJ, Meyers G, Tautz N (1998) Characterization of an autonomous subgenomic pestivirus RNA replicon. J Virol 72:2364–2372
Tomassini JE, Boots E, Gan L, Graham P, Munshi V, Wolanski B, Fay JF, Getty K, LaFemina R (2003) An in vitro Flaviviridae replicase system capable of authentic RNA replication. Virology 313:274–285
Wiskerchen M, Collett MS (1991) Pestivirus gene expression: protein p80 of bovine viral diarrhea virus is a proteinase involved in polyprotein processing. Virology 184:341–350
Warrener P, Collett MS (1995) Pestivirus NS3 (p80) protein possesses RNA helicase activity. J Virol 69:1720–1726
Tamura JK, Warrener P, Collett MS (1993) RNA-stimulated NTPase activity associated with the p80 protein of the pestivirus bovine viral diarrhea virus. Virology 193:1–10
Yamane D, Zahoor MA, Mohamed YM, Azab W, Kato K, Tohya Y, Akashi H (2009) Inhibition of sphingosine kinase by bovine viral diarrhea virus NS3 is crucial for efficient viral replication and cytopathogenesis. J Biol Chem 284:13648–13659
Tautz N, Kaiser A, Thiel HJ (2000) NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease–cofactor interactions. Virology 273:351–363
Mohamed YM, Bangphoomi N, Yamane D, Suda Y, Kato K, Horimoto T, Akashi H (2014) Physical interaction between bovine viral diarrhea virus nonstructural protein 4A and adenosine deaminase acting on RNA (ADAR). Arch Virol 159:1735–1741
Weiskircher E, Aligo J, Ning G, Konan KV (2009) Bovine viral diarrhea virus NS4B protein is an integral membrane protein associated with Golgi markers and rearranged host membranes. Virol J 6:185
Qu L, McMullan LK, Rice CM (2001) Isolation and characterization of noncytopathic pestivirus mutants reveals a role for nonstructural protein NS4B in viral cytopathogenicity. J Virol 75:10651–10662
Isken O, Langerwisch U, Schönherr R, Lamp B, Schröder K, Duden R, Rümenapf TH, Tautz N (2014) Functional characterization of bovine viral diarrhea virus nonstructural protein 5A by reverse genetic analysis and live cell imaging. J Virol 88:82–98
Zahoor MA, Yamane D, Mohamed YM, Suda Y, Kobayashi K, Kato K, Tohya Y, Akashi H (2010) Bovine viral diarrhea virus non-structural protein 5A interacts with NIK- and IKKbeta-binding protein. J Gen Virol 91:1939–1948
Lai VC, Kao CC, Ferrari E, Park J, Uss AS, Wright-Minogue J, Hong Z, Lau JY (1999) Mutational analysis of bovine viral diarrhea virus RNA-dependent RNA polymerase. J Virol 73:10129–10136
Zhong W, Gutshall LL, Del Vecchio AM (1998) Identification and characterization of an RNA-dependent RNA polymerase activity within the nonstructural protein 5B region of bovine viral diarrhea virus. J Virol 72:9365–9369
He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93
Lee YR, Lei HY, Liu MT, Wang JR, Chen SH, Jiang-Shieh YF, Lin YS, Yeh TM, Liu CC, Liu HS (2008) Autophagic machinery activated by dengue virus enhances virus replication. Virology 374:240–248
Dreux M, Chisari FV (2009) Autophagy proteins promote hepatitis C virus replication. Autophagy 5:1224–1225
Jin R, Zhu W, Cao S, Chen R, Jin H, Liu Y, Wang S, Wang W, Xiao G (2013) Japanese encephalitis virus activates autophagy as a viral immune evasion strategy. PLoS One 8:e52909
Liang Q, Luo Z, Zeng J, Chen W, Foo SS, Lee SA, Ge J, Wang S, Goldman SA, Zlokovic BV, Zhao Z, Jung JU (2016) Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. Cell Stem Cell 19:663–671
Pei J, Zhao M, Ye Z, Gou H, Wang J, Yi L, Dong X, Liu W, Luo Y, Liao M, Chen J (2014) Autophagy enhances the replication of classical swine fever virus in vitro. Autophagy 10:93–110
Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM (2011) Rab5 and Class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol 85:10561–10571
Wang L, Tian Y, Ou JJ (2015) HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog 11:e1004764
Fu Q, Shi H, Zhang H, Ren Y, Guo F, Qiao J, Jia B, Wang P, Chen C (2014) Autophagy during early stages contributes to bovine viral diarrhea virus replication in MDBK cells. J Basic Microbiol 54:1044–1052
Fu Q, Shi H, Ren Y, Guo F, Ni W, Qiao J, Wang P, Zhang H, Chen C (2014) Bovine viral diarrhea virus infection induces autophagy in MDBK cells. J Microbiol 52:619–625
Zhou Y, Ren Y, Cong Y, Mu Y, Yin R, Ding Z (2017) Autophagy induced by bovine viral diarrhea virus infection counteracts apoptosis and innate immune activation. Arch Virol 162:3103–3118
Fu Q, Shi H, Shi M, Meng L, Bao H, Zhang G, Ren Y, Zhang H, Guo F, Qiao J, Jia B, Wang P, Ni W, Sheng J, Chen C (2014) Roles of bovine viral diarrhea virus envelope glycoproteins in inducing autophagy in MDBK cells. Microb Pathog 76:61–66
Tanida I, Ueno T, Kominami E (2008) LC3 and autophagy. In: Deretic V (ed) Autophagosome and phagosome. Humana Press, New York, pp 77–88
Nagai M, Sakoda Y, Mori M, Hayashi M, Kida H, Akashi H (2003) Insertion of cellular sequence and RNA recombination in the structural protein coding region of cytopathogenic bovine viral diarrhoea virus. J Gen Virol 84:447–452
Rajput MKS, Abdelsalam K, Darweesh MF, Braun LJ, Kerkvliet J, Hoppe AD, Chase CCL (2017) Both cytopathic and non-cytopathic bovine viral diarrhea virus (BVDV) induced autophagy at a similar rate. Vet Immunol Immunopathol 193–194:1–9
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752
Djavaheri-Mergny M, Maiuri MC, Kroemer G (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29:1717–1719
Zhou F, Yang Y, Xing D (2011) Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J 278:403–413
Suda Y, Yamane D, Zahoor MA, Mohamed YM, Murakami S, Kato K, Akashi H, Horimoto T (2016) Unique localization of bovine viral diarrhea virus non-structural NS4B protein in infected cells. J Adv Agric 6:913–921
Zaffagnini G, Martens S (2016) Mechanisms of selective autophagy. J Mol Biol 428:1714–1724
Acknowledgements
We thank Dr. Atsushi Miyawaki (Riken, Japan) for the Venus/pCS2 plasmid.
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Suda, Y., Murakami, S. & Horimoto, T. Bovine viral diarrhea virus non-structural protein NS4B induces autophagosomes in bovine kidney cells. Arch Virol 164, 255–260 (2019). https://doi.org/10.1007/s00705-018-4045-x
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DOI: https://doi.org/10.1007/s00705-018-4045-x