Scheidel2016 - In Silico Knockout Studies of Xenophagy Capturing of Salmonella

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Short description

Xenophagy, also known as antibacterial autophagy, is a process of capturing and eliminating cytosolic pathogens, like Salmonella. Salmonella is the best-studied model organism for xenophagy. We present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data and contains all known processes of Salmonella xenophagy in epithelial. The model comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. The Petri net is connected, covered by T-invariants, and each T-invariant has a meaningful biological interpretation. We checked the model structure for consistencies and correctness. We found 16 basic functional modules, which describe different pathways of the autophagic capturing of Salmonella and reflect the basic dynamics of the system. The PN model of Salmonella xenophagy comprises 61 places, including nine logical places, and 69 transitions connected by 184 arcs.

Format
SBML (L3V1)
Related Publication
  • In Silico Knockout Studies of Xenophagic Capturing of Salmonella.
  • Dikic I
  • PLoS computational biology , 12/ 2016 , Volume 12 , Issue 12 , pages: e1005200
  • Molecular Bioinformatics, Institute of Computer Science, Johann Wolfgang Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
  • The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway.
Contributors
Nasrin Alikhani Chamgordani, Rahuman Sheriff, Tung Nguyen

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Hannig(geb Scheidel)2016 - In Silico Knockout Studies of Xenophagic Capturing of Salmonella, Petri Nets.xml SBML L3V1 model file 119.47 KB Preview | Download

  • Model originally submitted by : Nasrin Alikhani Chamgordani
  • Submitted: Apr 16, 2019 12:22:09 PM
  • Last Modified: May 13, 2019 10:22:54 PM
Revisions
  • Version: 20 public model Download this version
    • Submitted on: May 13, 2019 10:22:54 PM
    • Submitted by: Tung Nguyen
    • With comment: Edited model metadata online.
  • Version: 16 public model Download this version
    • Submitted on: Apr 16, 2019 12:22:09 PM
    • Submitted by: Nasrin Alikhani Chamgordani
    • With comment: Model revised without commit message