Abstract
SummaryThrough a network of progressively maturing vesicles, the endosomal system connects the cell’s interior with extracellular space. Intriguingly, this network exhibits a bilateral architecture, comprised of a relatively immobile perinuclear vesicle “cloud” and a highly dynamic peripheral contingent. How this spatiotemporal organization is achieved and what function(s) it curates is unclear. Here, we reveal the endoplasmic reticulum (ER)-located ubiquitin ligase Ring finger protein 26 (RNF26) as the global architect of the entire endosomal system, including the trans-Golgi network (TGN). To specify perinuclear vesicle coordinates, catalytically competent RNF26 recruits and ubiquitinates the scaffold p62/sequestosome 1 (p62/SQSTM1), in turn attracting ubiquitin-binding domains (UBDs) of various vesicle adaptors. Consequently, RNF26 restrains fast transport of diverse vesicles through a common molecular mechanism operating at the ER membrane, until the deubiquitinating enzyme USP15 opposes RNF26 activity to allow vesicle release into the cell’s periphery. By drawing the endosomal system’s architecture, RNF26 orchestrates endosomal maturation and trafficking of cargoes, including signaling receptors, in space and time.
Highlights
Visual inspection of a typical cell reveals canonical arrangements of membrane-enclosed organelles
Given that late endosomes (LEs) constitute central nodes within the endoand exocytic vesicular network (Huotari and Helenius, 2011), we mined a genome-wide small interfering RNA-based screen for novel factors controlling LE biology (Paul et al, 2011), where silencing the RING finger ubiquitin ligase Ring finger protein 26 (RNF26) was shown to severely disrupt the intracellular LE organization, leading to marked dispersion of LEs throughout the cytoplasm and even to the tips of cells, without significantly impacting cell shape (Figures 1B–1D; Movies S1A and S1B). These observations cast RNF26 as a potent candidate for control of the LE compartment architecture, prompting us to investigate the role of RNF26 in the organization and function of the perinuclear (PN) cloud
Cells depleted of RNF26 exhibited an expanded periphery and increased mobility of the LTV contingent relative to control, blurring the PN/PP distinction (Figures 1E and 1F, bottom right panels; Movies S2B and S2C, Lysotracker; Movies S2D and S2E, mCherryCD63)
Summary
Visual inspection of a typical cell reveals canonical arrangements of membrane-enclosed organelles. The trans-Golgi network (TGN) vesicles disseminate biosynthetic cargoes to their sites of function throughout the cell (Waguri et al, 2003). On the other side of vesicle traffic, endosomes originating from the plasma membrane carry internalized cargoes to the lysosome for degradation or spare them through diversion to recycling (Raiborg and Stenmark, 2009). The roads traveled by endosomes time intracellular signaling cascades (Scita and Di Fiore, 2010) and tune specialized functions, such as antigen processing and pathogen clearance in immune cells (Blum et al, 2013). How cells sense and manipulate the location of individual vesicles in space and time to suit their global housekeeping and environmental demands is unclear
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