ROLE OF THE PROTEASOME IN MEMBRANE EXTRACTION OF A SHORT-LIVED ER-TRANSMEMBRANE PROTEIN

Selective degradation of proteins at the endoplasmic reticulum (ER-ass ociated degradation) is thought to proceed largely via the cytosolic u biquitin-proteasome pathway. Recent data have indicated that the dislo cation of short-lived integral-membrane proteins to the cytosolic prot eolytic system may require components of the Sec61 translocon. Here we show that the proteasome itself can participate in the extraction of an ER-membrane protein from the lipid bilayer. In yeast mutants expres sing functionally attenuated proteasomes, degradation of a short-lived doubly membrane-spanning protein proceeds rapidly through the N-termi nal cytosolic domain of the substrate, but slows down considerably whe n continued degradation of the molecule requires membrane extraction. Thus, proteasomes engaged in ER degradation can directly process trans membrane proteins through a mechanism in which the dislocation of the substrate and its proteolysis are coupled. We therefore propose that t he retrograde transport of short-lived substrates may be driven throug h the activity of the proteasome.