Dataset Information

Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis.

ABSTRACT:

Background

Given its recent rapid development and the central role that modeling plays in the discipline, systems biology clearly needs methods for automated modeling of dynamical systems. Process-based modeling focuses on explanatory models of dynamical systems; it constructs such models from measured time-course data and formalized modeling knowledge. In this paper, we apply process-based modeling to the practically relevant task of modeling the Rab5-Rab7 conversion switch in endocytosis. The task is difficult due to the limited observability of the system variables and the noisy measurements, which pose serious challenges to the process of model selection. To address these issues, we propose a domain-specific model selection criteria that take into account knowledge about the necessary properties of the simulated model behavior.

Results

In a series of modeling experiments, we compare the results of process-based modeling obtained with different model selection criteria. The first is the standard maximum likelihood criterion based solely on least-squares model error. The second one is a parsimony-based criterion that also takes into account model complexity. We also introduce three domain-specific criteria based on domain expert expectations about the simulated behavior of an endocytosis model. According to the first criterion, 90 of the candidate models are indistinguishable. Furthermore, taking into account the complexity of the model does not lead to better model selection. However, the use of domain-specific criteria results in a remarkable improvement over the other two model selection criteria.

Conclusions

We demonstrate the applicability of process-based modeling to the task of modeling the Rab5-Rab7 dynamics in endocytosis. Our experiments show that the domain-specific criteria outperform the standard domain-independent criteria for model selection. We also find that some of the model structures discarded as implausible in previous studies lead to the expected Rab5-Rab7 switch behavior.

SUBMITTER: Tanevski J

PROVIDER: S-EPMC4482292 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis.

Tanevski Jovan J Todorovski Ljupčo L Kalaidzidis Yannis Y Džeroski Sašo S

BMC systems biology 20150626

<h4>Background</h4>Given its recent rapid development and the central role that modeling plays in the discipline, systems biology clearly needs methods for automated modeling of dynamical systems. Process-based modeling focuses on explanatory models of dynamical systems; it constructs such models from measured time-course data and formalized modeling knowledge. In this paper, we apply process-based modeling to the practically relevant task of modeling the Rab5-Rab7 conversion switch in endocytos ...[more]

PMID: 26112042

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Project description:The members of Flaviviridae utilize several endocytic pathways to enter a variety of host cells. Our previous work showed that classical swine fever virus (CSFV) enters porcine kidney (PK-15) cells through a clathrin-dependent pathway that requires Rab5 and Rab7. The entry mechanism for CSFV into other cell lines remains unclear, for instance, porcine alveolar macrophages (3D4/21 cells). More importantly, the trafficking of CSFV within endosomes controlled by Rab GTPases is unknown in 3D4/21 cells. In this study, entry and postinternalization of CSFV were analyzed using chemical inhibitors, RNA interference, and dominant-negative (DN) mutants. Our data demonstrated that CSFV entry into 3D4/21 cells depends on caveolae, dynamin, and cholesterol but not clathrin or macropinocytosis. The effects of DN mutants and knockdown of four Rab proteins that regulate endosomal trafficking were examined on CSFV infection, respectively. The results showed that Rab5, Rab7, and Rab11, but not Rab9, regulate CSFV endocytosis. Confocal microscopy showed that virus particles colocalize with Rab5, Rab7, or Rab11 within 30 min after virus entry and further with lysosomes, suggesting that after internalization CSFV moves to early, late, and recycling endosomes and then into lysosomes before the release of the viral genome. Our findings provide insights into the life cycle of pestiviruses in macrophages.IMPORTANCE Classical swine fever, is caused by classical swine fever virus (CSFV). The disease is notifiable to World Organisation for Animal Health (OIE) in most countries and causes significant financial losses to the pig industry globally. Understanding the processes of CSFV endocytosis and postinternalization will advance our knowledge of the disease and provide potential novel drug targets against CSFV. With this objective, we used systematic approaches to dissect these processes in CSFV-infected 3D4/21 cells. The data presented here demonstrate for the first time to our knowledge that CSFV is able to enter cells via caveola-mediated endocytosis that requires Rab5, Rab7 and Rab11, in addition to the previously described classical clathrin-dependent pathway that requires Rab5 and Rab7. The characterization of CSFV entry will further promote our current understanding of Pestivirus cellular entry pathways and provide novel targets for antiviral drug development.

Dataset Information

Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis.

Background

Results

Conclusions

Publications

Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis.

Similar Datasets

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