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SUMMARY:Milstein Lecture 2013:  Sorting out protein traffic: Ubiquitin-med
 iated endocytosis and a membrane protien’s final ESCRT - Scott Emr\, Cor
 nell University
DTSTART:20130926T151500Z
DTEND:20130926T170000Z
UID:TALK45172@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:Down-regulation of cell surface receptors and transporters is 
 mediated by a series of membrane trafficking steps including ubiquitin-med
 iated endocytosis\, ESCRT-mediated cargo(Ub) recognition\, sorting and pac
 kaging into vesicles that bud into the lumen of the endosome (ILVs)\, and 
 endosome-lysosome fusion. We have focused our efforts on two stages of thi
 s pathway:\n  1) Ub-mediated endocytosis - We have shown that the E3 ubiqu
 itin ligase Rsp5\, the yeast homolog of Nedd4\, is a key mediator of prote
 in quality control at the PM. Proteotoxic stress triggers global activatio
 n of Rsp5-dependent ubiquitination\, endocytosis\, and lysosomal trafficki
 ng of PM proteins. Yeast mutants defective in this process are highly sens
 itive to proteotoxic stress. This stress-induced endocytosis system is med
 iated by a family of Rsp5 adaptors known as arrestin-related trafficking a
 daptors (or ARTs)\, which target Rsp5 ubiquitin ligase activity to specifi
 c PM proteins. We propose that the ubiquitin-mediated ART-Rsp5 network pro
 tects the cell from proteotoxic stress by limiting the toxic accumulation 
 of misfolded integral membrane proteins in the PM.\n   2) ILV formation - 
 The endosomal sorting complexes required for transport (ESCRTs) have emerg
 ed as key cellular machinery that drive topologically unique membrane defo
 rmation and scission events. These five protein complexes function at the 
 endosome as a ubiquitin-dependent protein sorting machine which recognizes
  and sorts Ub-cargo into vesicles that bud into the lumen of the endosome 
 (ILVs). We have evidence indicating that the ESCRT-III complex functions a
 s a vesicle budding machine. Soluble ESCRT-III subunits assemble in vitro 
 on lipid monolayers to generate long ~9nm-wide protofilaments composed of 
 two ~4nm sub-filaments. These protofilaments form 3-D helices that can sta
 bilize the necks of membrane invaginations. Understanding how the ESCRT-II
 I polymer interacts with membranes\, promoting and stabilizing membrane de
 formation\, is an important step in elucidating ILV formation. We have ide
 ntified an essential N-terminal motif on Snf7 that anchors the ESCRT-III p
 olymer to the membrane. We propose that ESCRT-III utilizes membrane insert
 ion and oligomeric scaffolding to drive vesicle formation.  \n
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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