HLA-DR Chains Enter into an Aggregated Complex Containing GRP-78/BiP Prior to Their Degradation by the Pre-Golgi Degradative Pathway (*)

Abstract

HLA class II molecules are membrane proteins which are assembled in the endoplasmic reticulum shortly after synthesis of the α and β and invariant chain (Ii) monomers. DRβ chains, in the absence of DRα, are rapidly and completely degraded by the pre-Golgi degradative pathway. Here we have examined those factors which target DRβ chains for degradation in a DRα deficient cell line, 9.22.3. The DRβ monomers in 9.22.3 were initially incorporated into a proteinaceous complex containing BiP. With time, the DRβ complexes were further aggregated. In wild type cells, which can assemble DRα-β dimers, the secondary phase of aggregation of DRβ was not seen. Additional evidence that aggregation of DRβ in 9.22.3 cells was progressive was that a more mature form of DRβ was found exclusively in the largest DRβ complexes. Furthermore, the most highly aggregated DRβ chains were degraded more rapidly than bulk DRβ chains. These data suggest that DRβ aggregates are intermediates in the pre-Golgi pathway of DRβ degradation. They further suggest that formation of large DRβ aggregates is a proximal event to DRβ degradation. We conclude that DRβ chains are targeted for degradation as a consequence of a change of state, coincident with their aggregation into slow forming, high molecular weight complexes.