Rapamycin and ZSTK474 can have differential effects at different post‑infection time‑points regarding CVB3 replication and CVB3‑induced autophagy

Chang,Huan; Tian,Lang; Chen,Jia; Tang,Anliu; Li,Chunyun; Li,Zhuoying; Yang,Zuocheng

doi:10.3892/mmr.2018.9037

Rapamycin and ZSTK474 can have differential effects at different post‑infection time‑points regarding CVB3 replication and CVB3‑induced autophagy

Authors:
- Huan Chang
- Lang Tian
- Jia Chen
- Anliu Tang
- Chunyun Li
- Zhuoying Li
- Zuocheng Yang
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Affiliations: Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: May 17, 2018 https://doi.org/10.3892/mmr.2018.9037
Pages: 1088-1094

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Abstract

Coxsackievirus B3 (CVB3) infection has been shown to stimulate autophagy. We have demonstrated that the inhibition of phosphoinositide 3‑kinase (PI3K)/protein kinase B/mammalian target of rapamycin complex (mTORC) signaling pathway could affect the autophagic reaction induced by CVB3 infection in our previous study. However, the processes associating autophagy and CVB3 replication remain to be determined. In the present study, CVB3‑induced autophagy and its impact on viral replication were investigated. Rapamycin (inhibitor of mTOR) and ZSTK474 (inhibitor of PI3K) were used to change the autophagic reaction caused by CVB3 in Hela cells at different post‑infection (p.i.) time points (6, 9, 12 and 24 h p.i.), meanwhile, we detected the CVB3 mRNA replication and CVB3 capsid protein VP1 expression following the change of autophagy. Here, it was showed that ZSTK474 and Rapamycin promoted CVB3‑induced autophagy, as well as decreasing CVB3 mRNA replication and CVB3 capsid protein VP1 expression at 6 and 9 h p.i. ZSTK474 also alleviated CVB3‑induced autophagy, and decreased CVB3 mRNA replication and VP1 expression at 12 and 24 h p.i. However, Rapamycin continued to promote CVB3‑induced autophagy and increase CVB3 mRNA replication at 12 and 24 h p.i, as well as increase VP1 expression at 12 h, but not at 24 h, p.i. In the present study, we found Rapamycin and ZSTK474 have differential effects at different p.i. time‑points regarding CVB3 replication and CVB3‑induced autophagy. This indicates that the association between CVB3‑induced autophagy and viral replication depends on the infection time. During the early course of infection, autophagy may help host cells clear the virus, thereby providing protection, whereas when the infection time increases, autophagy may be exploited for viral replication.

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1	Mizushima N: Autophagy: Process and function. Genes Dev. 21:2861–2873. 2007. View Article : Google Scholar : PubMed/NCBI
2	Dice JF: Chaperone-mediated autophagy. Autophagy. 3:295–299. 2007. View Article : Google Scholar : PubMed/NCBI
3	Pauly M, Assense A, Rondon A, Thomas A, Dubouchaud H, Freyssenet D, Benoit H, Castells J and Flore P: High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation. Sci Rep. 7:436632017. View Article : Google Scholar : PubMed/NCBI
4	Eisenstein M: Molecular biology: Remove, reuse, recycle. Nature. 514:S2–S4. 2014. View Article : Google Scholar : PubMed/NCBI
5	Garber K: Autophagy. Explaining exercise. Science. 335:2812012. View Article : Google Scholar : PubMed/NCBI
6	García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, et al: Autophagy maintains stemness by preventing senescence. Nature. 529:37–42. 2016. View Article : Google Scholar : PubMed/NCBI
7	Levine B, Mizushima N and Virgin HW: Autophagy in immunity and inflammation. Nature. 469:323–335. 2011. View Article : Google Scholar : PubMed/NCBI
8	Randow F and Münz C: Autophagy in the regulation of pathogen replication and adaptive immunity. Trends Immunol. 33:475–487. 2012. View Article : Google Scholar : PubMed/NCBI
9	Lee HK, Lund JM, Ramanathan B, Mizushima N and Iwasaki A: Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 315:1398–1401. 2007. View Article : Google Scholar : PubMed/NCBI
10	Su C, Zhan G and Zheng C: Evasion of host antiviral innate immunity by HSV-1, an update. Virol J. 13:382016. View Article : Google Scholar : PubMed/NCBI
11	Kudchodkar SB and Levine B: Viruses and autophagy. Rev Med Virol. 19:359–378. 2009. View Article : Google Scholar : PubMed/NCBI
12	Liao YH, Xia N, Zhou SF, Tang TT, Yan XX, Lv BJ, Nie SF, Wang J, Iwakura Y, Xiao H, et al: Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol. 59:420–429. 2012. View Article : Google Scholar : PubMed/NCBI
13	O'Connell D and Liang C: Autophagy interaction with herpes simplex virus type-1 infection. Autophagy. 12:451–459. 2016. View Article : Google Scholar : PubMed/NCBI
14	Doria A, Gatto M and Punzi L: Autophagy in human health and disease. N Engl J Med. 368:18452013. View Article : Google Scholar : PubMed/NCBI
15	Deretic V and Levine B: Autophagy, immunity, and microbial adaptations. Cell Host Microbe. 5:527–549. 2009. View Article : Google Scholar : PubMed/NCBI
16	Virgin HW and Levine B: Autophagy genes in immunity. Nat Immunol. 10:461–470. 2009. View Article : Google Scholar : PubMed/NCBI
17	Fader CM, Aguilera MO and Colombo MI: Autophagy response: Manipulating the mTOR-controlled machinery by amino acids and pathogens. Amino Acids. 47:2101–2112. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zhou XJ and Zhang H: Autophagy in immunity: Implications in etiology of autoimmune/autoinflammatory diseases. Autophagy. 8:1286–1299. 2012. View Article : Google Scholar : PubMed/NCBI
19	Scharl M and Rogler G: Inflammatory bowel disease: Dysfunction of autophagy? Dig Dis. 30 Suppl 3:S12–S19. 2012. View Article : Google Scholar
20	Puri P and Chandra A: Autophagy modulation as a potential therapeutic target for liver diseases. J Clin Exp Hepatol. 4:51–59. 2014. View Article : Google Scholar : PubMed/NCBI
21	Zhong L, Hu J, Shu W, Gao B and Xiong S: Epigallocatechin-3-gallate opposes HBV-induced incomplete autophagy by enhancing lysosomal acidification, which is unfavorable for HBV replication. Cell Death Dis. 6:e17702015. View Article : Google Scholar : PubMed/NCBI
22	De Leo A, Colavita F, Ciccosanti F, Fimia GM, Lieberman PM and Mattia E: Inhibition of autophagy in EBV-positive Burkitt's lymphoma cells enhances EBV lytic genes expression and replication. Cell Death Dis. 6:e18762015. View Article : Google Scholar : PubMed/NCBI
23	Li J, Liu Y, Wang Z, Liu K, Wang Y, Liu J, Ding H and Yuan Z: Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol. 85:6319–6333. 2011. View Article : Google Scholar : PubMed/NCBI
24	Watson RO, Manzanillo PS and Cox JS: Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell. 150:803–815. 2012. View Article : Google Scholar : PubMed/NCBI
25	Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth M, et al: Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature. 480:113–117. 2011. View Article : Google Scholar : PubMed/NCBI
26	Liu J, Wang H, Gu J, Deng T, Yuan Z, Hu B, Xu Y, Yan Y, Zan J, Liao M, et al: BECN1-dependent CASP2 incomplete autophagy induction by binding to rabies virus phosphoprotein. Autophagy. 13:739–753. 2017. View Article : Google Scholar : PubMed/NCBI
27	Garmaroudi FS, Marchant D, Hendry R, Luo H, Yang D, Ye X, Shi J and McManus BM: Coxsackievirus B3 replication and pathogenesis. Future Microbiol. 10:629–653. 2015. View Article : Google Scholar : PubMed/NCBI
28	Sin J, Mangale V, Thienphrapa W, Gottlieb RA and Feuer R: Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis. Virology. 484:288–304. 2015. View Article : Google Scholar : PubMed/NCBI
29	Chen Z, Yang L, Liu Y, Tang A, Li X, Zhang J and Yang Z: LY294002 and Rapamycin promote coxsackievirus-induced cytopathic effect and apoptosis via inhibition of PI3K/AKT/mTOR signaling pathway. Mol Cell Biochem. 385:169–177. 2014. View Article : Google Scholar : PubMed/NCBI
30	Zhang HM, Ye X, Su Y, Yuan J, Liu Z, Stein DA and Yang D: Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1. J Virol. 84:8446–8459. 2010. View Article : Google Scholar : PubMed/NCBI
31	Zhai X, Bai B, Yu B, Wang T, Wang H, Wang Y, Li H, Tong L, Wang Y, Zhang F, et al: Coxsackievirus B3 induces autophagic response in cardiac myocytes in vivo. Biochemistry (Mosc). 80:1001–1009. 2015. View Article : Google Scholar : PubMed/NCBI
32	Xin L, Xiao Z, Ma X, He F, Yao H and Liu Z: Coxsackievirus B3 induces crosstalk between autophagy and apoptosis to benefit its release after replicating in autophagosomes through a mechanism involving caspase cleavage of autophagy-related proteins. Infect Genet Evol. 26:95–102. 2014. View Article : Google Scholar : PubMed/NCBI
33	Robinson SM, Tsueng G, Sin J, Mangale V, Rahawi S, McIntyre LL, Williams W, Kha N, Cruz C, Hancock BM, et al: Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog. 10:e10040452014. View Article : Google Scholar : PubMed/NCBI
34	Li X, Li Z, Zhou W, Xing X, Huang L, Tian L, Chen J, Chen C, Ma X and Yang Z: Overexpression of 4EBP1, p70S6K, Akt1 or Akt2 differentially promotes Coxsackievirus B3-induced apoptosis in HeLa cells. Cell Death Dis. 4:e803–e809. 2013. View Article : Google Scholar : PubMed/NCBI
35	Xin L, Ma X, Xiao Z, Yao H and Liu Z: Coxsackievirus B3 induces autophagy in HeLa cells via the AMPK/MEK/ERK and Ras/Raf/MEK/ERK signaling pathways. Infect Genet Evol. 36:46–54. 2015. View Article : Google Scholar : PubMed/NCBI
36	Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T, et al: In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 15:4649–4664. 2009. View Article : Google Scholar : PubMed/NCBI