REMOVAL AND DEGRADATION OF THE FREE MHC CLASS-II BETA-CHAIN IN THE ENDOPLASMIC-RETICULUM REQUIRES PROTEASOMES AND IS ACCELERATED BY BFA

We have studied the degradation of the free major histocompatibility c omplex (MHC) class II beta subunit in the ER. Domain swapping experime nts demonstrate that both the intra- and extracellular domain determin e the rate of degradation. Recently, it has been shown that some ER-re tained proteins are exported from the ER by the translocon followed by deglycosylation and degradation in the cytosol by proteasomes. Degrad ation of the beta chain follows a different route. The proteasome is i nvolved hut inhibition of the proteasome by lactacystin does not resul t in deglycosylation and export to the cytosol, Instead, the beta chai n is retained in the ER implying that extraction of the beta chain fro m the ER membrane requires proteasome activity. Surprisingly, brefeldi n A accelerates the degradation of the beta chain by the proteasome, T his suggests that various processes outside the ER are involved in ER- degradation. The ER is the site from where misfolded class II beta cha ins enter a proteasome-dependent degradation pathway.