Actin-Regulator Feedback Interactions during Endocytosis. 2016

Xinxin Wang, and Brian J Galletta, and John A Cooper, and Anders E Carlsson
Department of Physics, Washington University, St. Louis, Missouri.

Endocytosis mediated by clathrin, a cellular process by which cells internalize membrane receptors and their extracellular ligands, is an important component of cell signaling regulation. Actin polymerization is involved in endocytosis in varying degrees depending on the cellular context. In yeast, clathrin-mediated endocytosis requires a pulse of polymerized actin and its regulators, which recruit and activate the Arp2/3 complex. In this article, we seek to identify the main protein-protein interactions that 1) cause actin and its regulators to appear in pulses, and 2) determine the effects of key mutations and drug treatments on actin and regulator assembly. We perform a joint modeling/experimental study of actin and regulator dynamics during endocytosis in the budding yeast Saccharomyces cerevisiae. We treat both a stochastic model that grows an explicit three-dimensional actin network, and a simpler two-variable Fitzhugh-Nagumo type model. The models include a negative-feedback interaction of F-actin onto the Arp2/3 regulators. Both models explain the pulse time courses and the effects of interventions on actin polymerization: the surprising increase in the peak F-actin count caused by reduced regulator branching activity, the increase in F-actin resulting from slowing of actin disassembly, and the increased Arp2/3 regulator lifetime resulting from latrunculin treatment. In addition, they predict that decreases in the regulator branching activity lead to increases in accumulation of regulators, and we confirmed this prediction with experiments on yeast harboring mutations in the Arp2/3 regulators, using quantitative fluorescence microscopy. Our experimental measurements suggest that the regulators act quasi-independently, in the sense that accumulation of a particular regulator is most strongly affected by mutations of that regulator, as opposed to the others.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004705 Endocytosis Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis. Endocytoses
D000072417 Protein Domains Discrete protein structural units that may fold independently of the rest of the protein and have their own functions. Peptide Domain,Protein Domain,Domain, Peptide,Domain, Protein,Domains, Peptide,Domains, Protein,Peptide Domains
D000199 Actins Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or F-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or G-actin. In conjunction with MYOSINS, actin is responsible for the contraction and relaxation of muscle. F-Actin,G-Actin,Actin,Isoactin,N-Actin,alpha-Actin,alpha-Isoactin,beta-Actin,gamma-Actin,F Actin,G Actin,N Actin,alpha Actin,alpha Isoactin,beta Actin,gamma Actin
D012441 Saccharomyces cerevisiae A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement. Baker's Yeast,Brewer's Yeast,Candida robusta,S. cerevisiae,Saccharomyces capensis,Saccharomyces italicus,Saccharomyces oviformis,Saccharomyces uvarum var. melibiosus,Yeast, Baker's,Yeast, Brewer's,Baker Yeast,S cerevisiae,Baker's Yeasts,Yeast, Baker
D013269 Stochastic Processes Processes that incorporate some element of randomness, used particularly to refer to a time series of random variables. Process, Stochastic,Stochastic Process,Processes, Stochastic
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D025461 Feedback, Physiological A mechanism of communication with a physiological system for homeostasis, adaptation, etc. Physiological feedback is mediated through extensive feedback mechanisms that use physiological cues as feedback loop signals to control other systems. Feedback, Biochemical,Feedback Inhibition, Biochemical,Feedback Regulation, Biochemical,Feedback Stimulation, Biochemical,Negative Feedback, Biochemical,Positive Feedback, Biochemical,Biochemical Feedback,Biochemical Feedback Inhibition,Biochemical Feedback Inhibitions,Biochemical Feedback Regulation,Biochemical Feedback Regulations,Biochemical Feedback Stimulation,Biochemical Feedback Stimulations,Biochemical Feedbacks,Biochemical Negative Feedback,Biochemical Negative Feedbacks,Biochemical Positive Feedback,Biochemical Positive Feedbacks,Feedback Inhibitions, Biochemical,Feedback Regulations, Biochemical,Feedback Stimulations, Biochemical,Feedback, Biochemical Negative,Feedback, Biochemical Positive,Feedbacks, Biochemical,Feedbacks, Biochemical Negative,Feedbacks, Biochemical Positive,Feedbacks, Physiological,Inhibition, Biochemical Feedback,Inhibitions, Biochemical Feedback,Negative Feedbacks, Biochemical,Physiological Feedback,Physiological Feedbacks,Positive Feedbacks, Biochemical,Regulation, Biochemical Feedback,Regulations, Biochemical Feedback,Stimulation, Biochemical Feedback,Stimulations, Biochemical Feedback

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