title: Cargo-dependent degradation of ESCRT-I as a feedback mechanism to modulate endosomal sorting.
abstract: 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.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
authors.forename: Lene
authors.initials: L
authors.lastname: Malerød
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Pedersen
authors.forename: Catherine Elisabeth
authors.initials: CE
authors.lastname: Sem Wegner
authors.forename: Viola Hélène
authors.initials: VH
authors.lastname: Lobert
authors.forename: Edward
authors.initials: E
authors.lastname: Leithe
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Edgar
authors.initials: E
authors.lastname: Rivedal
authors.forename: Knut
authors.initials: K
authors.lastname: Liestøl
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
mesh_terms: D002460:Cell Line; D016895:Culture Media, Serum-Free; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099177:Tsg101 Protein
chemical_list: D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000099177:Tsg101 Protein