Cargo-dependent degradation of ESCRT-I as a feedback mechanism to modulate endosomal sorting

Traffic. 2011 Sep;12(9):1211-26. doi: 10.1111/j.1600-0854.2011.01220.x. Epub 2011 Jun 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Culture Media, Serum-Free
  • Cytoplasmic Vesicles / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Endosomes / metabolism*
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism*
  • Feedback, Physiological*
  • Humans
  • Lysosomes / metabolism
  • Protein Transport / physiology
  • RNA, Small Interfering / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • RNA, Small Interfering
  • Transcription Factors
  • Tsg101 protein
  • Epidermal Growth Factor
  • ErbB Receptors