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Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10.
- Source :
-
PLoS computational biology [PLoS Comput Biol] 2021 May 20; Vol. 17 (5), pp. e1007986. Date of Electronic Publication: 2021 May 20 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- The adaptive immune system serves as a potent and highly specific defense mechanism against pathogen infection. One component of this system, the effector T cell, facilitates pathogen clearance upon detection of specific antigens by the T cell receptor (TCR). A critical process in effector T cell activation is transmission of signals from the TCR to a key transcriptional regulator, NF-κB. The transmission of this signal involves a highly dynamic process in which helical filaments of Bcl10, a key protein constituent of the TCR signaling cascade, undergo competing processes of polymeric assembly and macroautophagy-dependent degradation. Through computational analysis of three-dimensional, super-resolution optical micrographs, we quantitatively characterize TCR-stimulated Bcl10 filament assembly and length dynamics, and demonstrate that filaments become shorter over time. Additionally, we develop an image-based, bootstrap-like resampling method that demonstrates the preferred association between autophagosomes and both Bcl10-filament ends and punctate-Bcl10 structures, implying that autophagosome-driven macroautophagy is directly responsible for Bcl10 filament shortening. We probe Bcl10 polymerization-depolymerization dynamics with a stochastic Monte-Carlo simulation of nucleation-limited filament assembly and degradation, and we show that high probabilities of filament nucleation in response to TCR engagement could provide the observed robust, homogeneous, and tunable response dynamic. Furthermore, we demonstrate that the speed of filament disassembly preferentially at filament ends provides effective regulatory control. Taken together, these data suggest that Bcl10 filament growth and degradation act as an excitable system that provides a digital response mechanism and the reliable timing critical for T cell activation and regulatory processes.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Algorithms
Animals
Autophagosomes immunology
Autophagosomes metabolism
B-Cell CLL-Lymphoma 10 Protein chemistry
B-Cell CLL-Lymphoma 10 Protein genetics
Cell Line
Computational Biology
Computer Simulation
Mice
Models, Biological
Monte Carlo Method
Polymerization
Proteolysis
Receptors, Antigen, T-Cell metabolism
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Signal Transduction
B-Cell CLL-Lymphoma 10 Protein metabolism
Lymphocyte Activation
T-Lymphocytes immunology
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7358
- Volume :
- 17
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PLoS computational biology
- Publication Type :
- Academic Journal
- Accession number :
- 34014917
- Full Text :
- https://doi.org/10.1371/journal.pcbi.1007986