Abstract
Proteins that fail to fold or assemble in the endoplasmic reticulum (ER) are destroyed by cytoplasmic proteasomes through a process known as ER-associated degradation. Substrates of this pathway are initially sequestered within the ER lumen and must therefore be dislocated across the ER membrane to be degraded. It has been proposed that generation of bicellar structures during lipid droplet formation may provide an "escape hatch" through which misfolded proteins, toxins, and viruses can exit the ER. We have directly tested this hypothesis by exploiting yeast strains defective in lipid droplet formation. Our data demonstrate that lipid droplet formation is dispensable for the dislocation of a plant toxin and the degradation of both soluble and integral membrane glycoproteins.
Highlights
Secreted and transmembrane proteins are co-translationally inserted into the endoplasmic reticulum (ER),3 where they are folded, modified, and assembled into higher order complexes prior to transport to their final destinations
Little is known about how lipid droplets (LDs) form, and Ploegh [7] hypothesized that generation of bicellar structures during LD formation could result in transient pores, or “escape hatches,” in the ER membrane, allowing the escape of luminal ER-associated degradation (ERAD) substrates and/or the direct extraction of polytopic substrates associated with the LD membrane
Immunofluorescence analyses of the BODIPY 493/503stained LDs demonstrated that LDs were present in wild-type (WT) yeast and the strain lacking the ERAD ubiquitin ligase Hrd1p but were absent from the LD⌬ strain (Fig. 1A)
Summary
Secreted and transmembrane proteins are co-translationally inserted into the endoplasmic reticulum (ER),3 where they are folded, modified, and assembled into higher order complexes prior to transport to their final destinations. Polytopic ER-resident membrane proteins including Sec61p [3], Derlins [4, 5], and Hrd1p [6] have been suggested, largely on the basis of their polytopic membrane-spanning topology, their proximity to other membrane-associated components of the ERAD system, and the ability to co-precipitate or be crosslinked to putative dislocation intermediates, to be structural elements of a transmembrane channel that mediates substrate
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