These authors contributed equally to this work.
Cargo-Dependent Degradation of ESCRT-I as a Feedback Mechanism to Modulate Endosomal Sorting
Article first published online: 13 JUN 2011
© 2011 John Wiley & Sons A/S
Volume 12, Issue 9, pages 1211–1226, September 2011
How to Cite
Malerød, L., Pedersen, N. M., Sem Wegner, C. E., Lobert, V. H., Leithe, E., Brech, A., Rivedal, E., Liestøl, K. and Stenmark, H. (2011), Cargo-Dependent Degradation of ESCRT-I as a Feedback Mechanism to Modulate Endosomal Sorting. Traffic, 12: 1211–1226. doi: 10.1111/j.1600-0854.2011.01220.x
- Issue published online: 11 AUG 2011
- Article first published online: 13 JUN 2011
- Accepted manuscript online: 12 MAY 2011 11:15AM EST
- Received 23 September 2010, revised and accepted for publication 11 May 2011, uncorrected manuscript published online 12 May 2011, published online 13 June 2011
- endosomal sorting;
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.