Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism

Harrison M. York (), Kunaal Joshi, Charles S. Wright, Laura Z. Kreplin, Samuel J. Rodgers, Ullhas K. Moorthi, Hetvi Gandhi, Abhishek Patil, Christina A. Mitchell, Srividya Iyer-Biswas () and Senthil Arumugam ()
Additional contact information
Harrison M. York: Monash University
Kunaal Joshi: Purdue University
Charles S. Wright: Purdue University
Laura Z. Kreplin: Monash University
Samuel J. Rodgers: Monash University
Ullhas K. Moorthi: Monash University
Hetvi Gandhi: Monash University
Abhishek Patil: Monash University
Christina A. Mitchell: Monash University
Srividya Iyer-Biswas: Purdue University
Senthil Arumugam: Monash University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Endosomal maturation is critical for robust and timely cargo transport to specific cellular compartments. The most prominent model of early endosomal maturation involves a phosphoinositide-driven gain or loss of specific proteins on individual endosomes, emphasising an autonomous and stochastic description. However, limitations in fast, volumetric imaging long hindered direct whole cell-level measurements of absolute numbers of maturation events. Here, we use lattice light-sheet imaging and bespoke automated analysis to track individual very early (APPL1-positive) and early (EEA1-positive) endosomes over the entire population, demonstrating that direct inter-endosomal contact drives maturation between these populations. Using fluorescence lifetime, we show that this endosomal interaction is underpinned by asymmetric binding of EEA1 to very early and early endosomes through its N- and C-termini, respectively. In combination with agent-based simulation which supports a ‘trigger-and-convert’ model, our findings indicate that APPL1- to EEA1-positive maturation is driven not by autonomous events but by heterotypic EEA1-mediated interactions, providing a mechanism for temporal and population-level control of maturation.

Date: 2023
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DOI: 10.1038/s41467-023-40428-1

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