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The Synergistic Role of Tip α, Nucleolin and Ras in Helicobacter pylori Infection Regulates the Cell Fate Towards Inflammation or Apoptosis

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Abstract

Infection with Helicobacter pylori (H. pylori) leads to a fork in the road situation where it is critical and complex to judge the fate of the cell. We propose for the first time an in silico representation of a protein level network model that can unfold the mystery behind the cell fate decision between inflammation or cell proliferation or cell death. Upon infection TNF inducible protein α (Tip α) is internalised after binding with the cell surface receptor Nucleolin which is overexpressed on the cell surface thereby activating the Ras pathway. Tip α, Nucleolin and Ras decides the cell fate for apoptosis or abnormal cell proliferation along with ulcers in the gastric tract, hence we term it as the “death triad”, which otherwise triggers the inflammatory pathway through downstream signalling of NF-κβ. A series of proteins involved in the signalling cascade are portrayed through compartmentalization of the bacteria and the gut wall. The depicted network works synchronously toward an overarching goal of deciding between apoptosis or inflammation or proliferation. The model has been validated by simulating it with existing transcriptomic data along with clinical findings from patients infected with H. pylori across different regions in India. The results clearly indicate that for a short period of time there is increased binding of Tip α to Nucleolin and the receptor starts to saturate. This increases the tenacity of binding and the cell triggers an inflammatory cascade reaction which involves proinflammatory cytokines such as TNF α thereby progressing to inflammation by activating NF-κβ downstream. On the other hand, Ras involved in interaction with nucleolin can be present both in its activated or inactivated state. Binding of Tip α as a monomer leads to desensitization of Nucleolin leading to cell survival and proliferation.

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Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Morgner A et al (2001) Helicobacter pylori associated gastric B cell MALT lymphoma: predictive factors for regression. Gut 48(3):290–292

    Article  CAS  Google Scholar 

  2. Bakri MM (2013) Prevalence of Helicobacter pylori infection and the incidence of ureA and clarithromycin resistance gene 23S rRNA genotypes status in Saudi Arabia. Saudi J Biol Sci 20(1):75–78

    Article  CAS  Google Scholar 

  3. Ferreira AC et al (2008) Helicobacter and gastric malignancies. Helicobacter 13:28–34

    Article  CAS  Google Scholar 

  4. Atherton JC et al (1997) Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 112(1):92–99

    Article  CAS  Google Scholar 

  5. Yamaoka Y et al (1999) Relationship between Helicobacter pylori iceA, cagA, and vacA status and clinical outcome: studies in four different countries. J Clin Microbiol 37(7):2274–2279

    Article  CAS  Google Scholar 

  6. Suganuma M et al (2008) TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells. Int J Cancer 123(1):117–122

    Article  CAS  Google Scholar 

  7. Tsuge H et al (2009) Structural basis for the Helicobacter pylori-carcinogenic TNF-α-inducing protein. Biochem Biophys Res Commun 388(2):193–198

    Article  CAS  Google Scholar 

  8. Godlewska R et al (2008) Tip-α (hp0596 gene product) is a highly immunogenic Helicobacter pylori protein involved in colonization of mouse gastric mucosa. Curr Microbiol 56(3):279–286

    Article  CAS  Google Scholar 

  9. Polk DB, Peek RM (2010) Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 10(6):403–414

    Article  CAS  Google Scholar 

  10. Censini S et al (1996) Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci 93(25):14648–14653

    Article  CAS  Google Scholar 

  11. Sayed IM et al (2020) Helicobacter pylori infection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells. J Biol Chem 295(32):11082–11098

    Article  CAS  Google Scholar 

  12. Derakhshan MH et al (2006) Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with Helicobacter pylori. J Clin Pathol 59(12):1293–1299

    Article  CAS  Google Scholar 

  13. Ugrinova I et al (2018) Chapter four—multifaceted nucleolin protein and its molecular partners in oncogenesis. In: Donev R (ed) Advances in protein chemistry and structural biology. Academic Press, Cambridge, pp 133–164

    Google Scholar 

  14. Masiuk M (2008) Nucleolin—characteristics of protein and its role in biology of cancers and viral infections. Adv Cell Biol 1:1–19

    Article  Google Scholar 

  15. Srivastava M, Pollard HB (1999) Molecular dissection of nucleolin’s role in growth and cell proliferation: new insights. FASEB J 13(14):1911–1922

    Article  CAS  Google Scholar 

  16. Reyes-Reyes EM, Akiyama SK (2008) Cell-surface nucleolin is a signal transducing P-selectin binding protein for human colon carcinoma cells. Exp Cell Res 314(1112):2212–2223

    Article  CAS  Google Scholar 

  17. Watanabe T et al (2010) Nucleolin on the cell surface as a new molecular target for gastric cancer treatment. Biol Pharm Bull 33(5):796–803

    Article  CAS  Google Scholar 

  18. Schokoroy S et al (2013) Disrupting the oncogenic synergism between nucleolin and ras results in cell growth inhibition and cell death. PLoS ONE 8(9):e75269

    Article  CAS  Google Scholar 

  19. Novere NL et al (2005) Minimum information requested in the annotation of biochemical models (MIRIAM). Nat Biotech 23(12):1509–1515

    Article  Google Scholar 

  20. Hucka M et al (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19(4):524–531

    Article  CAS  Google Scholar 

  21. Farin K et al (2011) Oncogenic synergism between ErbB1, nucleolin, and mutant ras. Can Res 71(6):2140–2151

    Article  CAS  Google Scholar 

  22. Merrell DS et al (2003) pH-regulated gene expression of the gastric pathogen Helicobacter pylori. Infect Immun 71(6):3529–3539

    Article  CAS  Google Scholar 

  23. Girvan AC et al (2006) AGRO100 inhibits activation of nuclear factor-κB (NF-κB) by forming a complex with NF-κB essential modulator (NEMO) and nucleolin. Mol Cancer Ther 5(7):1790–1799

    Article  CAS  Google Scholar 

  24. Mukherjee S, Zhang Y (2011) Protein–protein complex structure predictions by multimeric threading and template recombination. Structure 19(7):955–966

    Article  CAS  Google Scholar 

  25. Tamura K et al (2007) MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 24(8):1596–1599

    Article  CAS  Google Scholar 

  26. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucl Acids Res 29:e45

    Article  CAS  Google Scholar 

  27. Fernández-Medarde A, Santos E (2011) Ras in cancer and developmental diseases. Genes Cancer 2(3):344–358

    Article  Google Scholar 

  28. Papamichael K, Konstantopoulos P, Mantzaris GJ (2014) Helicobacter pylori infection and inflammatory bowel disease: is there a link? World J Gastroenterol WJG 20(21):6374–6385

    Article  Google Scholar 

  29. Capitani N, Codolo G, Vallese F, Minervini G, Grassi A, Cianchi F, Troilo A, Fischer W, Zanotti G, Baldari CT, de Bernard M, D’Elios MM (2019) The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling. Cell Microbiol 21(5):e13006

    Article  Google Scholar 

  30. Tajrishi MM, Tuteja R, Tuteja N (2011) Nucleolin. Commun Integr Biol 4(3):267–275

    Article  CAS  Google Scholar 

  31. Takahashi G et al (1993) Effect of granulocyte-macrophage colony-stimulating factor and interleukin-3 on interleukin-8 production by human neutrophils and monocytes. Blood 81(2):357–364

    CAS  PubMed  Google Scholar 

  32. Hovanessian AG et al (2010) Surface expressed nucleolin is constantly induced in tumor cells to mediate calcium-dependent ligand internalization. PLoS ONE 5(12):e15787

    Article  CAS  Google Scholar 

  33. Lamb A et al (2009) Helicobacter pylori CagA activates NF-κB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep 10(11):1242–1249

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Dr Ashok K. Chauhan, Founder President, Amity University, for providing the infrastructure and support to carry out our research work. We also thank, Mr Pranav Patni of Amity Institute of Biotechnology for his commendable help.

Funding

This study has been funded by ICMR (5/13/16/2015/NCD-III). Dr. Amlan Chakraborty is a postdoctoral research fellow and is funded through an NHMRC grant.

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Author notes

  1. Dr. Shweta Mahant and Dr. Amlan Chakraborty: co-first authors.

Authors and Affiliations

  1. Amity Institute of Biotechnology, Amity University, Noida, U.P, 201313, India

    Shweta Mahant, Shubham Mehra, Valentina Gehlot, Sudeep Bose & Rajashree Das

  2. Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Amlan Chakraborty

  3. Victorian Heart Institute, Monash University, Melbourne, VIC, 3800, Australia

    Amlan Chakraborty

  4. Centre of Bioinformatics, University of Allahabad, Prayagraj, U.P, 211002, India

    Anup Som

  5. Department of Gastroenterology, Manipal Hospital, Dwarka, New Delhi, 110075, India

    Kunal Das

  6. Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Kolkata, 700010, India

    Asish Kumar Mukhopadhyay

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  1. Shweta Mahant
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Contributions

RD and SB have given the concept of association between Tip α and Nucleolin. SM & AC have performed the experiments, analysed the data and drafted the manuscript. RD and VG have revised the manuscript. AS has done the part of the docking analysis. SM has done the part of the expression analysis. AKM has provided the samples for expression profiling. KD has conceptualised the idea clinically and corrected the manuscript.

Corresponding authors

Correspondence to Sudeep Bose or Rajashree Das.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

This study was approved by institutional ethical committee of Amity Institute of Biotechnology, Noida, U.P, dated 2-12-2015 and National Institute of Cholera and Enteric Diseases, Kolkata (A-1/2016-IEC, dated 22-12-2016).

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Mahant, S., Chakraborty, A., Som, A. et al. The Synergistic Role of Tip α, Nucleolin and Ras in Helicobacter pylori Infection Regulates the Cell Fate Towards Inflammation or Apoptosis. Curr Microbiol 78, 3720–3732 (2021). https://doi.org/10.1007/s00284-021-02626-2

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  • DOI: https://doi.org/10.1007/s00284-021-02626-2

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