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Regulated protein sorting in the endosomal system
01 Jan 2008
Abstract
Endocytosed proteins are either returned to the cell surface via a recycling pathway or are delivered to the lysosome/vacuole to be degraded. Endosomal sorting of the Saccharomyces cerevisiae high-affinity iron transporter, composed of the Fet3 and Ftr1 proteins, is regulated by available iron. The molecular mechanisms underlying the differential trafficking of the transporter based on this environmental cue have until now remained undefined. In iron-starved cells, Fet3p-Ftr1p is maintained on the plasma membrane via an endocytic recycling pathway. Endocytic recycling of Fet3p-Ftr1p requires the sorting nexin Grd19/Snx3p, the pentameric retromer complex, and the Ypt6p Golgi Rab GTPase module. Sorting into the recycling pathway is mediated by direct binding of Grd19/Snx3p to a recycling signal within the cytoplasmic C-terminal tail of Ftr1p. Retromer and Grd19/Snx3p co-localize in part to endosomal membranes where they are physically associated. Grd19/Snx3p thus functions as a cargo-specific adapter for retromer, conferring additional cargo selectivity on the complex. In contrast, when iron is provided to iron-starved cells, Fet3p-Ftr1p is internalized from the plasma membrane and is delivered to the lumen of the vacuole to be degraded. Iron-regulated degradation is mediated by the multivesicular body (MVB) sorting pathway. In mutant cells lacking the Rsp5p ubiquitin ligase or components of the MVB machinery, Fet3p-Ftrlp is constitutively sorted into the recycling pathway regardless of iron status. A mutant form of Fet3p-Ftrlp, in which all 22 cytosolic lysine residues have been replaced by arginines, is also constitutively recycled, and it accumulates transiently in an endosome to which a subunit of the MVB sorting receptor (Vps27p), Grd19/Snx3p, and retromer proteins all co-localize. This endosome is where regulated sorting of the iron transporter occurs, and the recycling and degradative pathways diverge from this point. Therefore, the MVB pathway and the retromer-dependent recycling pathway have functionally antagonistic roles at the same intracellular compartment in mediating iron-regulated trafficking of the Fet3p-Ftr1p transporter.
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Details
- Title
- Regulated protein sorting in the endosomal system
- Creators
- Todd Strochlic
- Resource Type
- Book
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Identifiers
- 9780549574651; 0549574654; 991020837832004721