Degradation of proteins from the ER of S-cerevisiae requires an intact unfolded protein response pathway

To dissect the requirements of membrane protein degradation from the ER, we expressed the mouse major histocompatibility complex class I heavy chain H -2K(b) in yeast. Like other proteins degraded from the ER, unassembled H-2K (b) heavy chains are not transported to the Golgi but are degraded in a pro teasome-dependent manner. The overexpression of H-2K(b) heavy chains induce s the unfolded protein response (UPR). In yeast mutants unable to mount the UPR, H-2K(b) heavy chains are greatly stabilized. This defect in degradati on is suppressed by the expression of the active form of Hac1p, the transcr iption factor that upregulates UPR-induced genes. These results indicate th at induction of the UPR is required for the degradation of protein substrat es from the ER.