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2016 ; 110
(6
): 1430-43
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Actin-Regulator Feedback Interactions during Endocytosis
#MMPMID27028652
Wang X
; Galletta BJ
; Cooper JA
; Carlsson AE
Biophys J
2016[Mar]; 110
(6
): 1430-43
PMID27028652
show ga
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.
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