1887

Abstract

Species A rotavirus (RVA) is one of the pathogens causing severe acute gastroenteritis in young children and animals worldwide. RVA replicates and assembles its immature particle within electron dense compartments known as viroplasm. Despite the importance of lipid droplet (LD) formation in the RVA viroplasm, the upstream molecules modulating LD formation have remained elusive. Here, we demonstrate that RVA infection reprogrammes sterol regulatory element binding proteins (SREBPs)-dependent lipogenic pathways in virus-infected cells. Interestingly, silencing of SREBPs significantly reduced RVA protein synthesis, genome replication and progeny virus production. Moreover, knockout of SREBP-1c gene conferred resistance to RVA-induced diarrhoea, reduction of RVA replication, and mitigation of small intestinal pathology in mice. This study identifies SREBPs-mediated lipogenic reprogramming in RVA-infected host cells for facilitating virus replication and SREBPs as a potential target for developing therapeutics against RVA infection.

Keyword(s): knockout , mice , rotavirus , SREBPs and viroplasm
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001757
2022-05-20
2024-12-08
Loading full text...

Full text loading...

References

  1. Chukkapalli V, Heaton NS, Randall G. Lipids at the interface of virus-host interactions. Curr Opin Microbiol 2012; 15:512–518 [View Article] [PubMed]
    [Google Scholar]
  2. Lorizate M, Kräusslich H-G. Role of lipids in virus replication. Cold Spring Harb Perspect Biol 2011; 3:a004820 [View Article] [PubMed]
    [Google Scholar]
  3. Henne WM, Reese ML, Goodman JM. The assembly of lipid droplets and their roles in challenged cells. EMBO J 2018; 37:12 [View Article] [PubMed]
    [Google Scholar]
  4. Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 2019; 20:137–155 [View Article] [PubMed]
    [Google Scholar]
  5. Jarc E, Petan T. Lipid droplets and the management of cellular stress. Yale J Biol Med 2019; 92:435–452 [PubMed]
    [Google Scholar]
  6. Saka HA, Valdivia R. Emerging roles for lipid droplets in immunity and host-pathogen interactions. Annu Rev Cell Dev Biol 2012; 28:411–437 [View Article] [PubMed]
    [Google Scholar]
  7. Farese RV, Walther TC. Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 2009; 139:855–860 [View Article] [PubMed]
    [Google Scholar]
  8. Herker E, Ott M. Emerging role of lipid droplets in host/pathogen interactions. J Biol Chem 2012; 287:2280–2287 [View Article] [PubMed]
    [Google Scholar]
  9. Roingeard P, Melo RCN. Lipid droplet hijacking by intracellular pathogens. Cell Microbiol 2017; 19: [View Article] [PubMed]
    [Google Scholar]
  10. Crawford SE, Desselberger U. Lipid droplets form complexes with viroplasms and are crucial for rotavirus replication. Curr Opin Virol 2016; 19:11–15 [View Article] [PubMed]
    [Google Scholar]
  11. Troeger C, Khalil IA, Rao PC, Cao S, Blacker BF et al. Rotavirus vaccination and the global burden of rotavirus diarrhea among children younger than 5 years. JAMA Pediatr 2018; 172:958–965 [View Article] [PubMed]
    [Google Scholar]
  12. Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013; 381:1405–1416 [View Article] [PubMed]
    [Google Scholar]
  13. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000-2013. Clin Infect Dis 2016; 1:S96–S105
    [Google Scholar]
  14. Dhama K, Chauhan RS, Mahendran M, Malik SVS. Rotavirus diarrhea in bovines and other domestic animals. Vet Res Commun 2009; 33:1–23 [View Article] [PubMed]
    [Google Scholar]
  15. Crawford SE, Ramani S, Tate JE, Parashar UD, Svensson L et al. Rotavirus infection. Nat Rev Dis Primers 2017; 3:17083 [View Article] [PubMed]
    [Google Scholar]
  16. Desselberger U. Rotaviruses. Virus Res 2014; 190:75–96 [View Article] [PubMed]
    [Google Scholar]
  17. Greenberg HB, Estes MK. Rotaviruses: from pathogenesis to vaccination. Gastroenterology 2009; 136:1939–1951 [View Article] [PubMed]
    [Google Scholar]
  18. Silvestri LS, Taraporewala ZF, Patton JT. Rotavirus replication: plus-sense templates for double-stranded RNA synthesis are made in viroplasms. J Virol 2004; 78:7763–7774 [View Article] [PubMed]
    [Google Scholar]
  19. Petrie BL, Greenberg HB, Graham DY, Estes MK. Ultrastructural localization of rotavirus antigens using colloidal gold. Virus Res 1984; 1:133–152 [View Article] [PubMed]
    [Google Scholar]
  20. Fabbretti E, Afrikanova I, Vascotto F, Burrone OR. Two non-structural rotavirus proteins, NSP2 and NSP5, form viroplasm-like structures in vivo. J Gen Virol 1999; 80 (Pt 2):333–339 [View Article] [PubMed]
    [Google Scholar]
  21. Eichwald C, Rodriguez JF, Burrone OR. Characterization of rotavirus NSP2/NSP5 interactions and the dynamics of viroplasm formation. J Gen Virol 2004; 85:625–634 [View Article] [PubMed]
    [Google Scholar]
  22. Carreño-Torres JJ, Gutiérrez M, Arias CF, López S, Isa P. Characterization of viroplasm formation during the early stages of rotavirus infection. Virol J 2010; 7:350 [View Article] [PubMed]
    [Google Scholar]
  23. Gaunt ER, Zhang Q, Cheung W, Wakelam MJO, Lever AML et al. Lipidome analysis of rotavirus-infected cells confirms the close interaction of lipid droplets with viroplasms. J Gen Virol 2013; 94:1576–1586 [View Article] [PubMed]
    [Google Scholar]
  24. Cheung W, Gill M, Esposito A, Kaminski CF, Courousse N et al. Rotaviruses associate with cellular lipid droplet components to replicate in viroplasms, and compounds disrupting or blocking lipid droplets inhibit viroplasm formation and viral replication. J Virol 2010; 84:6782–6798 [View Article] [PubMed]
    [Google Scholar]
  25. Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006; 124:35–46 [View Article] [PubMed]
    [Google Scholar]
  26. Xiao X, Song BL. SREBP: a novel therapeutic target. Acta Biochim Biophys Sin (Shanghai) 2013; 45:2–10 [View Article] [PubMed]
    [Google Scholar]
  27. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109:1125–1131 [View Article] [PubMed]
    [Google Scholar]
  28. Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol 2017; 13:710–730 [View Article] [PubMed]
    [Google Scholar]
  29. DeBose-Boyd RA, Ye J. SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond. Trends Biochem Sci 2018; 43:358–368 [View Article] [PubMed]
    [Google Scholar]
  30. Kleinfelter LM, Jangra RK, Jae LT, Herbert AS, Mittler E et al. Haploid genetic screen reveals a profound and direct dependence on cholesterol for hantavirus membrane fusion. mBio 2015; 6:e00801 [View Article] [PubMed]
    [Google Scholar]
  31. Park C-Y, Jun H-J, Wakita T, Cheong JH, Hwang SB. Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J Biol Chem 2009; 284:9237–9246 [View Article] [PubMed]
    [Google Scholar]
  32. Xiang Z, Qiao L, Zhou Y, Babiuk LA, Liu Q. Hepatitis C virus nonstructural protein-5A activates sterol regulatory element-binding protein-1c through transcription factor Sp1. Biochem Biophys Res Commun 2010; 402:549–553 [View Article] [PubMed]
    [Google Scholar]
  33. Meng Z, Liu Q, Sun F, Qiao L. Hepatitis C virus nonstructural protein 5A perturbs lipid metabolism by modulating AMPK/SREBP-1c signaling. Lipids Health Dis 2019; 18:191 [View Article] [PubMed]
    [Google Scholar]
  34. Olmstead AD, Knecht W, Lazarov I, Dixit SB, Jean F. Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents. PLoS Pathog 2012; 8:e1002468 [View Article] [PubMed]
    [Google Scholar]
  35. Hyrina A, Meng F, McArthur SJ, Eivemark S, Nabi IR et al. Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents. PLoS One 2017; 12:e0174483 [View Article] [PubMed]
    [Google Scholar]
  36. Wu Q, Li Z, Liu Q. An important role of SREBP-1 in HBV and HCV co-replication inhibition by PTEN. Virology 2018; 520:94–102 [View Article] [PubMed]
    [Google Scholar]
  37. Martín-Acebes MA, Jiménez de Oya N, Saiz J-C. Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses. Pharmaceuticals (Basel) 2019; 12:E97 [View Article] [PubMed]
    [Google Scholar]
  38. Petersen J, Drake MJ, Bruce EA, Riblett AM, Didigu CA et al. The major cellular sterol regulatory pathway is required for Andes virus infection. PLoS Pathog 2014; 10:e1003911 [View Article] [PubMed]
    [Google Scholar]
  39. Qiao L, Wu Q, Lu X, Zhou Y, Fernández-Alvarez A et al. SREBP-1a activation by HBx and the effect on hepatitis B virus enhancer II/core promoter. Biochem Biophys Res Commun 2013; 432:643–649 [View Article] [PubMed]
    [Google Scholar]
  40. Yuan S, Chu H, Chan JF-W, Ye Z-W, Wen L et al. SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target. Nat Commun 2019; 10:120 [View Article] [PubMed]
    [Google Scholar]
  41. Ward RL, Knowlton DR, Pierce MJ. Efficiency of human rotavirus propagation in cell culture. J Clin Microbiol 1984; 19:748–753 [View Article] [PubMed]
    [Google Scholar]
  42. Burns JW, Krishnaney AA, Vo PT, Rouse RV, Anderson LJ et al. Analyses of homologous rotavirus infection in the mouse model. Virology 1995; 207:143–153 [View Article] [PubMed]
    [Google Scholar]
  43. Li W, Zhou J, Xu Y. Study of the in vitro cytotoxicity testing of medical devices. Biomed Rep 2015; 3:617–620 [View Article] [PubMed]
    [Google Scholar]
  44. Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL et al. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 2002; 277:9520–9528 [View Article] [PubMed]
    [Google Scholar]
  45. Rong S, Cortés VA, Rashid S, Anderson NN, McDonald JG et al. Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice. Elife 2017; 6:e25015 [View Article] [PubMed]
    [Google Scholar]
  46. Zhang Z, Zou J, Shi Z, Zhang B, Etienne-Mesmin L et al. IL-22-induced cell extrusion and IL-18-induced cell death prevent and cure rotavirus infection. Sci Immunol 2020; 5:52 [View Article] [PubMed]
    [Google Scholar]
  47. Ramakrishnan MA. Determination of 50% endpoint titer using a simple formula. World J Virol 2016; 5:85–86 [View Article] [PubMed]
    [Google Scholar]
  48. Knipping K, McNeal MM, Crienen A, van Amerongen G, Garssen J et al. A gastrointestinal rotavirus infection mouse model for immune modulation studies. Virol J 2011; 8:109 [View Article] [PubMed]
    [Google Scholar]
  49. Boshuizen JA, Reimerink JHJ, Korteland-van Male AM, van Ham VJJ, Bouma J et al. Homeostasis and function of goblet cells during rotavirus infection in mice. Virology 2005; 337:210–221 [View Article] [PubMed]
    [Google Scholar]
  50. Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 2013; 153:112–125 [View Article] [PubMed]
    [Google Scholar]
  51. McDonough PM, Agustin RM, Ingermanson RS, Loy PA, Buehrer BM et al. Quantification of lipid droplets and associated proteins in cellular models of obesity via high-content/high-throughput microscopy and automated image analysis. Assay Drug Dev Technol 2009; 7:440–460 [View Article] [PubMed]
    [Google Scholar]
  52. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13:1016–1023 [View Article] [PubMed]
    [Google Scholar]
  53. Zhang Z, He G, Filipowicz NA, Randall G, Belov GA et al. Host Lipids in Positive-Strand RNA Virus Genome Replication. Front Microbiol 2019; 10:286 [View Article] [PubMed]
    [Google Scholar]
  54. Gaunt ER, Zhang Q, Cheung W, Wakelam MJO, Lever AML et al. Lipidome analysis of rotavirus-infected cells confirms the close interaction of lipid droplets with viroplasms. J Gen Virol 2013; 94:1576–1586 [View Article] [PubMed]
    [Google Scholar]
  55. Eichwald C, Rodriguez JF, Burrone OR. Characterization of rotavirus NSP2/NSP5 interactions and the dynamics of viroplasm formation. J Gen Virol 2004; 85:625–634 [View Article] [PubMed]
    [Google Scholar]
  56. Cloherty APM, Olmstead AD, Ribeiro CMS, Jean F. Hijacking of lipid droplets by Hepatitis C, Dengue and Zika Viruses—from viral Protein moonlighting to extracellular release. IJMS 2020; 21:7901 [View Article]
    [Google Scholar]
  57. Herms A, Bosch M, Reddy BJN, Schieber NL, Fajardo A et al. AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. Nat Commun 2015; 6:7176 [View Article] [PubMed]
    [Google Scholar]
  58. Chlanda P, Mekhedov E, Waters H, Sodt A, Schwartz C et al. Palmitoylation contributes to membrane curvature in influenza A virus assembly and hemagglutinin-mediated membrane fusion. J Virol 2017; 91:e00947-17 [View Article] [PubMed]
    [Google Scholar]
  59. Veit M. Palmitoylation of virus proteins. Biol Cell 2012; 104:493–515 [View Article] [PubMed]
    [Google Scholar]
  60. Laufman O, Perrino J, Andino R. Viral generated inter-organelle contacts redirect lipid flux for genome replication. Cell 2019; 178:275–289 [View Article] [PubMed]
    [Google Scholar]
  61. Ketter E, Randall G. Virus impact on lipids and membranes. Annu Rev Virol 2019; 6:319–340 [View Article] [PubMed]
    [Google Scholar]
  62. Park CY, Jun HJ, Wakita T, Cheong JH, Hwang SB. Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J Biol Chem 2009; 284:9237–9246 [View Article] [PubMed]
    [Google Scholar]
  63. Monson EA, Crosse KM, Duan M, Chen W, O’Shea RD et al. Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response. Nat Commun 2021; 12:2020 [View Article] [PubMed]
    [Google Scholar]
/content/journal/jgv/10.1099/jgv.0.001757
Loading
/content/journal/jgv/10.1099/jgv.0.001757
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error