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

• Published in: Current microbiology Vol. 78; no. 10; pp. 3720 - 3732
• Main Authors: Mahant, Shweta, Chakraborty, Amlan, Som, Anup, Mehra, Shubham, Das, Kunal, Mukhopadhyay, Asish Kumar, Gehlot, Valentina, Bose, Sudeep, Das, Rajashree
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2021; Springer Nature B.V
• Subjects: Apoptosis; Bacterial Proteins - metabolism; Binding; Biomedical and Life Sciences; Biotechnology; Cascade chemical reactions; Cell death; Cell fate; Cell growth; Cell proliferation; Cell surface; Cell survival; Cytokines; Desensitization; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Infections; Inflammation; Life Sciences; Microbiology; Nucleolin; Phosphoproteins; Proteins; Ras protein; ras Proteins - metabolism; Receptors; RNA-Binding Proteins; Signal transduction; Signaling; Tumor necrosis factor; Tumor Necrosis Factor-alpha; Ulcers
• DOI: 10.1007/s00284-021-02626-2
• ISSN: 0343-8651

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.