Abstract
Autophagy is a cellular catabolic process implicated in numerous physiological processes and pathological conditions, including infections. Viruses have evolved different strategies to modulate the autophagic process. Since the effects of rubella virus (RV) on autophagy have not yet been reported, we evaluated the autophagic activity in the Statens Seruminstitut Rabbit Cornea cell line infected with the To336 strain of RV. Our results showed that RV lowered the levels of microtubule-associated protein 1 light chain 3 B-II (LC3B-II) and the autophagy-related gene 12–autophagy-related gene 5 conjugate, inhibited the autophagic flux, suppressed the intracellular redistribution of LC3B, decreased both the average number and the size of autophagosomes per cell and impeded the formation of acidic vesicular organelles. Induction of autophagy by using rapamycin decreased both the viral yields and the apoptotic rates of infected cultures. Besides its cytoprotective effects, autophagy furnishes an important antiviral mechanism, inhibition of which may reorchestrate intracellular environment so as to better serve the unique requirements of RV replication. Together, our observations suggest that RV utilizes a totally different strategy to cope with autophagy than that evolved by other positive-stranded RNA viruses, and there is considerable heterogeneity among the members of the Togaviridae family in terms of their effects on the cellular autophagic cascade.
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References
Hobman T, Chantler J (2007) Rubella virus. In: Knipe DM, Howley PM (eds) Fields virology, 5th edn. Lippincott Williams and Wilkins, Philadelphia, pp 1070–1100
Lee JY, Bowden DS (2000) Rubella virus replication and links to teratogenicity. Clin Microbiol Rev 13:571–587
Frey TK (1994) Molecular biology of rubella virus. Adv Virus Res 44:69–160
Lee JY, Bowden DS, Marshall JA (1996) Membrane junctions associated with rubella virus infected cells. J Submicrosc Cytol Pathol 28:101–108
Pugachev KV, Frey TK (1998) Rubella virus induces apoptosis in culture cells. Virology 250:359–370
Megyeri K, Berencsi K, Halazonetis TD, Prendergast GC, Gri G, Plotkin SA, Rovera G, Gönczöl E (1999) Involvement of a p53-dependent pathway in rubella virus-induced apoptosis. Virology 259:74–84
Buzás K, Miczák A, Degré M, Megyeri K (2004) Rubella virus infection dysregulates the pattern of p63 expression. APMIS 112:656–662
Lee JY, Marshall JA, Bowden DS (1999) Localization of rubella virus core particles in Vero cells. Virology 265:110–119
Baron MD, Ebel T, Suomalainen M (1992) Intracellular transport of rubella virus structural proteins expressed from cloned cDNA. J Gen Virol 73:1073–1086
Shi J, Luo H (2012) Interplay between the cellular autophagy machinery and positive-stranded RNA viruses. Acta Biochim Biophys Sin 44:375–384
Dong X, Levine B (2013) Autophagy and viruses: adversaries or allies? J Innate Immun 5:480–493
Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131
Sarkar S (2013) Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 41:1103–1130
Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741
Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A (2010) Electron tomography reveals the endoplasmic reticulum as a membrane source for autophagosome formation. Autophagy 6:301–303
Hamasaki M, Shibutani ST, Yoshimori T (2013) Up-to-date membrane biogenesis in the autophagosome formation. Curr Opin Cell Biol 25(4):455–460
Fujita N, Hayashi-Nishino M, Fukumoto H, Omori H, Yamamoto A, Noda T, Yoshimori T (2008) An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol Biol Cell 19:4651–4659
Boyle KB, Randow F (2013) The role of ‘eat-me’ signals and autophagy cargo receptors in innate immunity. Curr Opin Microbiol 16:339–348
Schreiber A, Peter M (2014) Substrate recognition in selective autophagy and the ubiquitin–proteasome system. Biochim Biophys Acta 1843:163–181
Deretic V (2011) Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol Rev 240:92–104
Buchkovich NJ, Yu Y, Zampieri CA, Alwine JC (2008) The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nat Rev Microbiol 6:266–275
Deretic V, Saitoh T, Akira S (2013) Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722–737
Kudchodkar SB, Levine B (2009) Viruses and autophagy. Rev Med Virol 19:359–378
Rasband WS (1997–2012) ImageJ, U. S. National Institutes of Health, Bethesda, Maryland, USA. http://imagej.nih.gov/ij/
Mironova EV, Evstratova AA, Antonov SM (2007) A fluorescence vital assay for the recognition and quantification of excitotoxic cell death by necrosis and apoptosis using confocal microscopy on neurons in culture. J Neurosci Methods 163:1–8
Phillips CA, Melnick JL, Burkhardt M (1966) Isolation, propagation and neutralization of rubella virus in cultures of rabbit cornea (SIRC) cells. Proc Soc Exp Biol Med 122:783–786
Taylor MP, Kirkegaard K (2007) Modification of cellular autophagy protein LC3 by poliovirus. J Virol 81:12543–12553
Wong J, Zhang J, Si X, Gao G, Mao I, McManus BM, Luo H (2008) Autophagosome supports coxsackievirus B3 replication in host cells. J Virol 82:9143–9153
Klein KA, Jackson WT (2011) Human rhinovirus 2 induces the autophagic pathway and replicates more efficiently in autophagic cells. J Virol 85:9651–9654
Huang SC, Chang CL, Wang PS, Tsai Y, Liu HS (2009) Enterovirus 71-induced autophagy detected in vitro and in vivo promotes viral replication. J Med Virol 81:1241–1252
Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray RB (2012) Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol 86:8705–8712
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
Li JK, Liang JJ, Liao CL, Lin YL (2012) Autophagy is involved in the early step of Japanese encephalitis virus infection. Microbes Infect 14:159–168
Joubert PE, Werneke S, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow D, Albert ML (2012) Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy. Autophagy 8:1261–1263
Joubert PE, Werneke SW, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow DJ, Albert ML (2012) Chikungunya virus-induced autophagy delays caspase-dependent cell death. J Exp Med 209:1029–1047
Krejbich-Trotot P, Gay B, Li-Pat-Yuen G, Hoarau JJ, Jaffar-Bandjee MC, Briant L, Gasque P, Denizot M (2011) Chikungunya triggers an autophagic process which promotes viral replication. Virol J 8:432
Abraham R, Mudaliar P, Padmanabhan A, Sreekumar E (2013) Induction of cytopathogenicity in human glioblastoma cells by chikungunya virus. PLoS One 8:e75854
Rana J, Sreejith R, Gulati S, Bharti I, Jain S, Gupta S (2013) Deciphering the host-pathogen protein interface in chikungunya virus-mediated sickness. Arch Virol 158:1159–1172
Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth M, Forst CV, Wrana JL, Zhang YE, Luby-Phelps K, Xavier RJ, Xie Y, Levine B (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113–117
Orvedahl A, MacPherson S, Sumpter R Jr, Tallóczy Z, Zou Z, Levine B (2010) Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7:115–127
Sumpter R Jr, Levine B (2011) Selective autophagy and viruses. Autophagy 7:260–265
Cooray S, Jin L, Best JM (2005) The involvement of survival signaling pathways in rubella-virus induced apoptosis. Virol J 2:1
Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487–502
Bracho-Valdés I, Moreno-Alvarez P, Valencia-Martínez I, Robles-Molina E, Chávez-Vargas L, Vázquez-Prado J (2011) mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused. IUBMB Life 63:896–914
Fenton TR, Gout IT (2011) Functions and regulation of the 70 kDa ribosomal S6 kinases. Int J Biochem Cell Biol 43:47–59
Bincoletto C, Bechara A, Pereira GJ, Santos CP, Antunes F, Peixoto da-Silva J, Muler M, Gigli RD, Monteforte PT, Hirata H, Jurkiewicz A, Smaili SS (2013) Interplay between apoptosis and autophagy, a challenging puzzle: new perspectives on antitumor chemotherapies. Chem Biol Interact 206:279–288
Di Bartolomeo S, Nazio F, Cecconi F (2010) The role of autophagy during development in higher eukaryotes. Traffic 11:1280–1289
Acknowledgments
We would like to thank Gyöngyi Ábrahám for expert technical assistance. This work was supported by the TÁMOP-4.2.2/B-10/1-2010-0012 and TÁMOP4.2.2.A-11/1/KONV-2012-0035 programs of the Hungarian National Development Agency.
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Pásztor, K., Orosz, L., Seprényi, G. et al. Rubella virus perturbs autophagy. Med Microbiol Immunol 203, 323–331 (2014). https://doi.org/10.1007/s00430-014-0340-7
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DOI: https://doi.org/10.1007/s00430-014-0340-7