Enterovirus 71 VP1 promotes mouse Schwann cell autophagy via ER stress‑mediated PMP22 upregulation

  • Authors:
    • Peiqing Li
    • Sida Yang
    • Dandan Hu
    • Dan Wei
    • Jing Lu
    • Huanying Zheng
    • Shushan Nie
    • Guangming Liu
    • Haomei Yang
  • View Affiliations

  • Published online on: May 30, 2019     https://doi.org/10.3892/ijmm.2019.4218
  • Pages: 759-767
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Abstract

Enterovirus 71 (EV71) accounts for the majority of hand, foot and mouth disease‑related deaths due to fatal neurological complications. EV71 structural viral protein 1 (VP1) promotes viral replication by inducing autophagy in neuron cells, but the effect of VP1 on myelin cells is unclear. The present study aimed to investigate the role and mechanism of VP1 in autophagy of mouse Schwann cells. An EV71 VP1‑expressing vector (pEGFP‑C3‑VP1) was generated and transfected into mouse Schwann cells. Transmission electron microscopy and western blot analysis for microtubule‑associated protein 1 light chain 3 α (LC3) II (an autophagy marker) were used to assess autophagy. Reverse transcription‑quantitative PCR and immunofluorescence were performed to determine the expression of peripheral myelin protein 22 (PMP22). Small interfering RNA against PMP22 was used to investigate the role of PMP22 in mouse Schwann cell autophagy. Salubrinal [a selective endoplasmic reticulum (ER) stress inhibitor] was used to determine whether PMP22 expression was affected by ER stress. The present results indicated that VP1 promoted mouse Schwann cell autophagy. Overexpression of VP1 upregulated PMP22. PMP22 deficiency downregulated LC3II and thus inhibited autophagy. Furthermore, PMP22 expression was significantly suppressed by salubrinal. In conclusion, VP1 promoted mouse Schwann cell autophagy through upregulation of ER stress‑mediated PMP22 expression. Therefore, the VP1/ER stress/PMP22 autophagy axis may be a potential therapeutic target for EV71 infection‑induced fatal neuronal damage.

References

1 

Liu MY, Liu J, Lai W, Luo J, Liu Y, Vu GP, Yang Z, Trang P, Li H and Wu J: Characterization of enterovirus 71 infection and associated outbreak of Hand, Foot, and Mouth disease in shawo of China in 2012. Sci Rep. 6:384512016. View Article : Google Scholar : PubMed/NCBI

2 

Wang Y, Zou G, Xia A, Wang X, Cai J, Gao Q, Yuan S, He G, Zhang S, Zeng M and Altmeyer R: Enterovirus 71 infection in children with hand, foot, and mouth disease in Shanghai, China: Epidemiology, clinical feature and diagnosis. Virol J. 12:832015. View Article : Google Scholar : PubMed/NCBI

3 

Aswathyraj S, Arunkumar G, Alidjinou EK and Hober D: Hand, foot and mouth disease (HFMD): Emerging epidemiology and the need for a vaccine strategy. Med Microbiol Immunol. 205:397–407. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Shimizu H and Nakashima K: Surveillance of hand, foot, and mouth disease for a vaccine. Lancet Infect Dis. 14:262–263. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Zhang Y, Tan XJ, Wang HY, Yan DM, Zhu SL, Wang DY, Ji F, Wang XJ, Gao YJ, Chen L, et al: An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human entero-virus 71 in Shandong, China. J Clin Virol. 44:262–267. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Chong CY, Chan KP, Shah VA, Ng WY, Lau G, Teo TE, Lai SH and Ling AE: Hand, foot and mouth disease in Singapore: A comparison of fatal and non-fatal cases. Acta Paediatr. 92:1163–1169. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Sabanathan S, Tan le V, Thwaites L, Wills B, Qui PT and Rogier van Doorn H: Enterovirus 71 related severe hand, foot and mouth disease outbreaks in South-East Asia: Current situation and ongoing challenges. J Epidemiol Community Health. 68:500–502. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P and Ooi MH: Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 10:778–790. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Gui J, Liu Z, Zhang T, Hua Q, Jiang Z, Chen B, Gu H, Lv H and Dong C: Epidemiological characteristics and spatial-temporal clusters of hand, foot, and mouth disease in zhejiang province, China, 2008-2012. PLoS One. 10:e01391092015. View Article : Google Scholar : PubMed/NCBI

10 

Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, Chang Z, Liu F, Fang VJ, Zheng Y, et al: Hand, foot, and mouth disease in China, 2008-12: An epidemiological study. Lancet Infect Dis. 14:308–318. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Hsueh C, Jung SM, Shih SR, Kuo TT, Shieh WJ, Zaki S, Lin TY, Chang LY, Ning HC and Yen DC: Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: Report of an autopsy case with pathologic, immunofluorescence, and molecular studies. Mod Pathol. 13:1200–1205. 2000. View Article : Google Scholar : PubMed/NCBI

12 

Kuo RL, Kung SH, Hsu YY and Liu WT: Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol. 83:1367–1376. 2002. View Article : Google Scholar : PubMed/NCBI

13 

Li ML, Hsu TA, Chen TC, Chang SC, Lee JC, Chen CC, Stollar V and Shih SR: The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology. 293:386–395. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Yang SD, Li PQ, Li YM, Li W, Lai WY, Zhu CP, Tao JP, Deng L, Liu HS, Ma WC, et al: Clinical manifestations of severe enterovirus 71 infection and early assessment in a Southern China population. BMC Infect Dis. 17:1532017. View Article : Google Scholar : PubMed/NCBI

15 

Klionsky DJ: Autophagy: From phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 8:931–937. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Mizushima N and Klionsky DJ: Protein turnover via autophagy: Implications for metabolism. Annu Rev Nutr. 27:19–40. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Ebrahimi-Fakhari D, Wahlster L, Hoffmann GF and Kolker S: Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases. Pediatr Res. 75:217–226. 2014. View Article : Google Scholar

18 

Ginet V, Spiehlmann A, Rummel C, Rudinskiy N, Grishchuk Y, Luthi-Carter R, Clarke PG, Truttmann AC and Puyal J: Involvement of autophagy in hypoxic-excitotoxic neuronal death. Autophagy. 10:846–860. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, et al: Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 141:1146–1158. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1–222. 2016. View Article : Google Scholar : PubMed/NCBI

21 

Tanida I, Ueno T and Kominami E: LC3 and autophagy. Methods Mol Biol. 445:77–88. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Benito-Cuesta I, Diez H, Ordonez L and Wandosell F: Assessment of autophagy in neurons and brain tissue. Cells. 6:E252017. View Article : Google Scholar : PubMed/NCBI

23 

Huang SC, Chang CL, Wang PS, Tsai Y and Liu HS: Enterovirus 71-induced autophagy detected in vitro and in vivo promotes viral replication. J Med Virol. 81:1241–1252. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Lee YR, Wang PS, Wang JR and Liu HS: Enterovirus 71-induced autophagy increases viral replication and pathogenesis in a suckling mouse model. J Biomed Sci. 21:802014. View Article : Google Scholar : PubMed/NCBI

25 

Hu DD, Mai JN, He LY, Li PQ, Chen WX, Yan JJ, Zhu WD, Deng L, Wei D, Liu DH, et al: Glucocorticoids prevent enterovirus 71 capsid protein VP1 induced calreticulin surface exposure by alleviating neuronal ER stress. Neurotox Res. 31:204–217. 2017. View Article : Google Scholar

26 

Rashid HO, Yadav RK, Kim HR and Chae HJ: ER stress: Autophagy induction, inhibition and selection. Autophagy. 11:1956–1977. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Lin W and Popko B: Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci. 12:379–385. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Lee WS, Yoo WH and Chae HJ: ER stress and autophagy. Curr Mol Med. 15:735–745. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Cai Y, Arikkath J, Yang L, Guo ML, Periyasamy P and Buch S: Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy. 12:225–244. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Zou X, Xu J, Yao S, Li J, Yang Y and Yang L: Endoplasmic reticulum stress-mediated autophagy protects against lipopoly-saccharide-induced apoptosis in HL-1 cardiomyocytes. Exp Physiol. 99:1348–1358. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Cheng X, Liu H, Jiang CC, Fang L, Chen C, Zhang XD and Jiang ZW: Connecting endoplasmic reticulum stress to autophagy through IRE1/JNK/beclin-1 in breast cancer cells. Int J Mol Med. 34:772–781. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Snipes GJ, Suter U, Welcher AA and Shooter EM: Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J Cell Biol. 117:225–238. 1992. View Article : Google Scholar : PubMed/NCBI

33 

Pareek S, Suter U, Snipes GJ, Welcher AA, Shooter EM and Murphy RA: Detection and processing of peripheral myelin protein PMP22 in cultured Schwann cells. J Biol Chem. 268:10372–10379. 1993.PubMed/NCBI

34 

Ryan MC, Notterpek L, Tobler AR, Liu N and Shooter EM: Role of the peripheral myelin protein 22 N-linked glycan in oligomer stability. J Neurochem. 75:1465–1474. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY and Snipes GJ: Association of calnexin with mutant peripheral myelin protein-22 ex vivo: A basis for 'gain-of-function' ER diseases. Proc Natl Acad Sci USA. 99:9852–9857. 2002. View Article : Google Scholar

36 

Hara T, Hashimoto Y, Akuzawa T, Hirai R, Kobayashi H and Sato K: Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease. Sci Rep. 4:69922014. View Article : Google Scholar : PubMed/NCBI

37 

Shibutani ST and Yoshimori T: A current perspective of autophagosome biogenesis. Cell Res. 24:58–68. 2014. View Article : Google Scholar :

38 

Barth S, Glick D and Macleod KF: Autophagy: Assays and artifacts. J Pathol. 221:117–124. 2010. View Article : Google Scholar : PubMed/NCBI

39 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

40 

Shi M, Zhou Y, Cao L, Ding C, Ji Y, Jiang Q, Liu X, Li X, Hou X, Peng H and Shi W: Expression of enterovirus 71 capsid protein VP1 in Escherichia coli and its clinical application. Braz J Microbiol. 44:1215–1222. 2013. View Article : Google Scholar

41 

Lal SK, Kumar P, Yeo WM, Kar-Roy A and Chow VT: The VP1 protein of human enterovirus 71 self-associates via an interaction domain spanning amino acids 66-297. J Med Virol. 78:582–590. 2006. View Article : Google Scholar : PubMed/NCBI

42 

Puyal J, Ginet V, Grishchuk Y, Truttmann AC and Clarke PG: Neuronal autophagy as a mediator of life and death: Contrasting roles in chronic neurodegenerative and acute neural disorders. Neuroscientist. 18:224–236. 2012. View Article : Google Scholar

43 

Xi X, Zhang X, Wang B, Wang T, Wang J, Huang H, Wang J, Jin Q and Zhao Z: The Interplays between autophagy and apoptosis induced by enterovirus 71. PLoS One. 8:e569662013. View Article : Google Scholar : PubMed/NCBI

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August 2019
Volume 44 Issue 2

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Copy and paste a formatted citation
APA
Li, P., Yang, S., Hu, D., Wei, D., Lu, J., Zheng, H. ... Yang, H. (2019). Enterovirus 71 VP1 promotes mouse Schwann cell autophagy via ER stress‑mediated PMP22 upregulation. International Journal of Molecular Medicine, 44, 759-767. https://doi.org/10.3892/ijmm.2019.4218
MLA
Li, P., Yang, S., Hu, D., Wei, D., Lu, J., Zheng, H., Nie, S., Liu, G., Yang, H."Enterovirus 71 VP1 promotes mouse Schwann cell autophagy via ER stress‑mediated PMP22 upregulation". International Journal of Molecular Medicine 44.2 (2019): 759-767.
Chicago
Li, P., Yang, S., Hu, D., Wei, D., Lu, J., Zheng, H., Nie, S., Liu, G., Yang, H."Enterovirus 71 VP1 promotes mouse Schwann cell autophagy via ER stress‑mediated PMP22 upregulation". International Journal of Molecular Medicine 44, no. 2 (2019): 759-767. https://doi.org/10.3892/ijmm.2019.4218