MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-DEPENDENT UNFOLDING, TRANSPORT, AND DEGRADATION OF ENDOGENOUS PROTEINS

We have analyzed the ability of major histocompatibility (MHC) class I I molecules to capture proteins in the biosynthetic pathway and whethe r this may be associated with MHC class II dependent antigen processin g, When coexpressed with HLA-DR 4 molecules in HeLa cells, influenza h emagglutinin was inhibited from folding and trimerization in the biosy nthetic pathway, targeted to endosomal compartments, and rapidly degra ded. Due to the interaction with MHC class II molecules, therefore, un folded forms of hemagglutinin were bypassing the quality control mecha nism of the secretory pathway, More important, however, the transport, endocytosis, and rapid degradation of unfolded hemagglutinin in the p resence of MHC class II molecules suggest that proteins captured in th e endoplasmic reticulum by class II molecules may become substrates fo r antigen processing and presentation to CD4-positive T cells. In inse ct cells we show that this phenomenon is not restricted to a few prote ins such as hemagglutinin. A highly heterogeneous mixture of proteins from the endoplasmic reticulum including coexpressed hemagglutinin can form stable complexes with soluble HLA DR alpha and beta chains that were transported into the supernatant. This mechanism may gain biologi cal significance in abnormal situations associated with accumulation o f unfolded or malfolded proteins in the endoplasmic reticulum, for exa mple during viral infections.