Review
Endosomal “sort” of signaling control: The role of ESCRT machinery in regulation of receptor-mediated signaling pathways

https://doi.org/10.1016/j.semcdb.2017.08.012Get rights and content

Abstract

The endosomal sorting complexes required for transport (ESCRTs) machinery consists of four protein assemblies (ESCRT-0 to -III subcomplexes) which mediate various processes of membrane remodeling in the cell. In the endocytic pathway, ESCRTs sort cargo destined for degradation into intraluminal vesicles (ILVs) of endosomes. Cargos targeted by ESCRTs include various signaling molecules, mainly internalized cell-surface receptors but also some cytosolic proteins. It is therefore expected that aberrant trafficking caused by ESCRT dysfunction affects different signaling pathways. Here we review how perturbation of ESCRT activity alters intracellular transport of membrane receptors, causing their accumulation on endocytic compartments, decreased degradation and/or altered recycling to the plasma membrane. We further describe how perturbed trafficking of receptors impacts the activity of their downstream signaling pathways, with or without changes in transcriptional responses. Finally, we present evidence that ESCRT components can also control activity and intracellular distribution of cytosolic signaling proteins (kinases, other effectors and soluble receptors). The underlying mechanisms involve sequestration of such proteins in ILVs, their sorting for degradation or towards non-lysosomal destinations, and regulating their availability in various cellular compartments. All these ESCRT-mediated processes can modulate final outputs of multiple signaling pathways.

Introduction

The endosomal sorting complexes required for transport (ESCRTs) represent a cellular machinery composed of four protein assemblies (ESCRT-0, -I, -II and -III subcomplexes), mediating inward membrane budding during endosomal sorting [1], [2]. Along the endocytic pathway, ESCRT components act cooperatively to recognize and deliver cargo destined for lysosomal degradation into intraluminal vesicles (ILVs) of endosomes, generating multivesicular bodies (MVBs). Such cargo (usually ubiquitinated transmembrane proteins) is recognized by the early-acting ESCRT-0 and -I, with the help of ESCRT-II. Then, cargo is incorporated in ILVs by invagination of the endosomal limiting membrane, mediated by the late-acting ESCRT-III. Additionally, some ESCRT components participate in other membrane remodeling processes in the cell: cytokinetic abscission, budding of viruses and exovesicles, repair of the plasma membrane (PM), reformation and sealing of the nuclear envelope, and others [3], [4], [5], [6]. ESCRTs may also contribute to various steps of autophagosome formation [7], [8]. Moreover, some ESCRT components were described to translocate to the nucleus and directly regulate transcription [9], [10].

In this review we will describe how ESCRT-mediated sorting of receptors affects various signaling pathways. We will present the implications of ESCRT dysfunction upon endocytic trafficking of cell-surface receptors, and upon downstream signaling cascades, as well as transcriptional responses. We will also discuss other mechanisms whereby ESCRTs regulate the activity of various signaling mediators, such as sequestration and degradation of cytosolic proteins, sorting of soluble cargo and control over the activation of intracellular receptors.

Section snippets

A canonical role of ESCRTs in sorting of cell-surface receptors

Signaling-related functions of ESCRTs are studied mostly in the context of a crucial role played by this machinery during sorting of internalized cell-surface receptors into ILVs for lysosomal degradation. The ESCRT-mediated sorting contributes to the balance between degradation and recycling of receptors, which is critical for controlling their availability on the PM and hence directly regulates the magnitude and duration of signaling (Fig. 1). As discussed below, perturbation of ESCRT

Other roles of ESCRTs in regulation of signaling mediators

In addition to its established roles in degradation or recycling of membrane receptors, the ESCRT machinery may also control the turnover and availability of cytosolic molecules acting downstream of receptors, thereby affecting signal transduction processes (Fig. 1). Some mechanisms underlying these ESCRT activities will be reviewed using selected examples below.

Concluding remarks

Altogether, the multiple functions of the ESCRT machinery in cellular signaling derive mostly from its role in cargo sorting on the endosomal membranes. ESCRTs mediate trafficking of a broad range of cargo molecules, both membrane receptors and soluble proteins. It is therefore not surprising that the consequences of ESCRT dysfunction for signaling processes are wide-ranging. Still, it seems that in most cases, altered signaling results from aberrant trafficking and is determined by the

Acknowledgements

We thank M. Banach-Orłowska, J. Cendrowski, D. Zdżalik-Bielecka and K. Wojciechowska for critical reading of the manuscript. Work in the authors laboratory is supported by a MAESTRO grant (UMO-2011/02/A/NZ3/00149) to M.M, and by a Sonata grant (UMO-2016/21/D/NZ3/00637) to E.S, both from National Science Center, Poland, and by the TEAM programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund (TEAM/2016-2/15) to M.M. NBH was

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