SEC61P MEDIATES EXPORT OF A MISFOLDED SECRETORY PROTEIN FROM THE ENDOPLASMIC-RETICULUM TO THE CYTOSOL FOR DEGRADATION

Degradation of misfolded secretory proteins has long been assumed to o ccur in the lumen of the endoplasmic reticulum (ER). Recent evidence, however, suggests that such proteins are instead degraded by proteasom es in the cytosol, although it remains unclear how the proteins are tr ansported out of the ER, Here we provide the first genetic evidence th at Sec61p, the pore-forming subunit of the protein translocation chann el in the ER membrane, is directly involved in the export of misfolded secretory proteins. We describe two novel mutants in yeast Sec61p tha t are cold-sensitive for import into the ER in both intact yeast cells and a cell-free system, Microsomes derived from these mutants are def ective in exporting misfolded secretory proteins, These proteins becom e trapped in the ER and are associated with Sec61p, We conclude that m isfolded secretory proteins are exported for degradation from the ER t o the cytosol via channels formed by Sec61p.