Deliver on Time or Pay the Fine: Scheduling in Membrane Trafficking

Abstract

Membrane trafficking is all about time. Automation in such a biological process is crucial to ensure management and delivery of cellular cargoes with spatiotemporal precision. Shared molecular regulators and differential engagement of trafficking components improve robustness of molecular sorting. Sequential recruitment of low affinity protein complexes ensures directionality of the process and, concomitantly, serves as a kinetic proofreading mechanism to discriminate cargoes from the whole endocytosed material. This strategy helps cells to minimize losses and operating errors in membrane trafficking, thereby matching the appealed deadline. Here, we summarize the molecular pathways of molecular sorting, focusing on their timing and efficacy. We also highlight experimental procedures and genetic approaches to robustly probe these pathways, in order to guide mechanistic studies at the interface between biochemistry and quantitative biology.

Keywords: ESCRT; PtdIns(3)P; Rab11; Rab5; Rab7; commander; endosome; lipid rafts; retromer; sorting.

Figure 1

Schematic summary of techniques available for molecular sorting investigations.

Figure 2

Schematic representation of Commander, ESCRT and Retromer complexes at the sorting endosome. Transmembrane cargoes are directed to plasma membrane, Golgi and Lysosome are accumulated in endosome. In this membrane-bound compartment, the Commander complex, together with the SNX and WASH complexes, mediates the sorting of cargoes to the plasma membrane. In parallel, ESCRT complexes recognize and direct ubiquitylated protein towards the lysosome for degradation. The Retromer complex, in association with the SNX and WASH complexes, defines transport towards both Golgi and the plasma membrane through the association of different SNX proteins.

Figure 3

Schematic representation of the RABs-mediated recruitment of sorting machineries on the endosomal membrane. (Top) Recruitment of sorting machineries in function of RAB7. SNX and RAB7 recruitment on the membrane enriched in PtdIns(3)P that, in a sequential manner, mediate endosomal recycling. Activated RAB5 recruits Vps34 and induces PtdIns(3)P production, this event allows ESCRT0 to recognize ubiquitinated proteins on endosome membrane enriched in PtdIns(3)P and direct to lysosome for degradation.