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An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation.

ABSTRACT: Cytokinesis in fission yeast is controlled by the Septation Initiation Network (SIN), a protein kinase signaling network using the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this paper, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN.

SUBMITTER: Chasapi A

PROVIDER: S-EPMC4526654 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation.

Chasapi Anastasia A Wachowicz Paulina P Niknejad Anne A Collin Philippe P Krapp Andrea A Cano Elena E Simanis Viesturs V Xenarios Ioannis I

PloS one 20150805 8

Cytokinesis in fission yeast is controlled by the Septation Initiation Network (SIN), a protein kinase signaling network using the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this paper, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses C ...[more]

PMID: 26244885

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Project description:BackgroundIn cell signaling pathways, proteins interact with each other to determine cell fate in response to either cell-extrinsic (micro-environmental) or intrinsic cues. One of the well-studied pathways, the mitogen-activated protein kinase (MAPK) signaling pathway, regulates cell processes such as differentiation, proliferation, apoptosis, and survival in response to various micro-environmental stimuli in eukaryotes. Upon micro-environmental stimulus, receptors on the cell membrane become activated. Activated receptors initiate a cascade of protein activation in the MAPK pathway. This activation involves protein binding, creating scaffold proteins, which are known to facilitate effective MAPK signaling transduction.ResultsThis paper presents a novel mathematical model of a cell signaling pathway coordinated by protein scaffolding. The model is based on the extended Boolean network approach with stochastic processes. Protein production or decay in a cell was modeled considering the stochastic process, whereas the protein-protein interactions were modeled based on the extended Boolean network approach. Our model fills a gap in the binary set applied to previous models. The model simultaneously considers the stochastic process directly. Using the model, we simulated a simplified mitogen-activated protein kinase (MAPK) signaling pathway upon stimulation of both a single receptor at the initial time and multiple receptors at several time points. Our simulations showed that the signal is amplified as it travels down to the pathway from the receptor, generating substantially amplified downstream ERK activity. The noise generated by the stochastic process of protein self-activity in the model was also amplified as the signaling propagated through the pathway.ConclusionsThe signaling transduction in a simplified MAPK signaling pathway could be explained by a mathematical model based on the extended Boolean network model with a stochastic process. The model simulations demonstrated signaling amplifications when it travels downstream, which was already observed in experimental settings. We also highlight the importance of stochastic activity in regulating protein inactivation.

Project description:Aspergillus fumigatus is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the β-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of A. fumigatus with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the A. fumigatus SIN. These included the GTPase, SpgA, it's two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of spgA, byrA, or bubA resulted in no overt septation or echinocandin susceptibility phenotypes. In contrast, our data show that deletion of sepM or mobA largely phenocopies disruption of their SIN kinase binding partners, sepL and sidB, respectively. Reduced septum formation, echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.IMPORTANCESepta are important structural determinants of echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen Aspergillus fumigatus. Components of the septation machinery therefore represent promising novel antifungal targets to improve echinocandin activity and reduce virulence. However, little is known about septation regulation in A. fumigatus. Here, we characterize the predicted regulatory components of the A. fumigatus septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and echinocandin resistance, with MobA playing an essential role. Null mutants of mobA displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for A. fumigatus pathogenesis.

Dataset Information

An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation.

Publications

An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation.

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