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Cargo‐Dependent Degradation of ESCRT‐I as a Feedback Mechanism to Modulate Endosomal Sorting
Author(s) -
Malerød Lene,
Pedersen Nina Marie,
Sem Wegner Catherine Elisabeth,
Lobert Viola Hélène,
Leithe Edward,
Brech Andreas,
Rivedal Edgar,
Liestøl Knut,
Stenmark Harald
Publication year - 2011
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2011.01220.x
Subject(s) - escrt , endosome , tsg101 , microbiology and biotechnology , biology , downregulation and upregulation , biochemistry , microvesicles , intracellular , microrna , gene
Ligand‐mediated lysosomal degradation of growth factor receptors, mediated by the endosomal sorting complex required for transport (ESCRT) machinery, is a mechanism that attenuates the cellular response to growth factors. In this article, we present a novel regulatory mechanism that involves ligand‐mediated degradation of a key component of the sorting machinery itself. We have investigated the endosomal localization of subunits of the four ESCRTs—Hrs (ESCRT‐0), Tsg101 (ESCRT‐I), EAP30/Vps22 (ESCRT‐II) and charged multivesicular body protein 3/Vps24 (ESCRT‐III). All the components were detected on the limiting membrane of multivesicular endosomes (MVEs). Surprisingly, however, Tsg101 and other ESCRT‐I subunits were also detected within intraluminal vesicles (ILVs) of MVEs. Tsg101 was sequestered along with cargo during endosomal sorting into ILVs and further degraded in lysosomes. Importantly, ESCRT‐mediated downregulation of two distinct cargoes, epidermal growth factor receptor (EGFR) and connexin43, mutually made cells refractory to degradation of the other cargo. Our observations indicate that the degradation of a key ESCRT component along with cargo represents a novel feedback control of endosomal sorting by preventing collateral degradation of cell surface receptors following stimulation of one specific pathway.