University of Cambridge > Talks.cam > MRC LMB Seminar list > Milstein Lecture 2013: Sorting out protein traffic: Ubiquitin-mediated endocytosis and a membrane protien’s final ESCRT

Milstein Lecture 2013: Sorting out protein traffic: Ubiquitin-mediated endocytosis and a membrane protien’s final ESCRT

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Down-regulation of cell surface receptors and transporters is mediated by a series of membrane trafficking steps including ubiquitin-mediated endocytosis, ESCRT -mediated cargo(Ub) recognition, sorting and packaging into vesicles that bud into the lumen of the endosome (ILVs), and endosome-lysosome fusion. We have focused our efforts on two stages of this pathway: 1) Ub-mediated endocytosis – We have shown that the E3 ubiquitin ligase Rsp5, the yeast homolog of Nedd4, is a key mediator of protein quality control at the PM. Proteotoxic stress triggers global activation of Rsp5-dependent ubiquitination, endocytosis, and lysosomal trafficking of PM proteins. Yeast mutants defective in this process are highly sensitive to proteotoxic stress. This stress-induced endocytosis system is mediated by a family of Rsp5 adaptors known as arrestin-related trafficking adaptors (or ARTs), which target Rsp5 ubiquitin ligase activity to specific PM proteins. We propose that the ubiquitin-mediated ART -Rsp5 network protects the cell from proteotoxic stress by limiting the toxic accumulation of misfolded integral membrane proteins in the PM. 2) ILV formation – The endosomal sorting complexes required for transport (ESCRTs) have emerged as key cellular machinery that drive topologically unique membrane deformation 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 as 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 stabilize the necks of membrane invaginations. Understanding how the ESCRT -III polymer interacts with membranes, promoting and stabilizing membrane deformation, is an important step in elucidating ILV formation. We have identified an essential N-terminal motif on Snf7 that anchors the ESCRT -III polymer to the membrane. We propose that ESCRT -III utilizes membrane insertion and oligomeric scaffolding to drive vesicle formation.

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