HLA-DR beta chains enter into an aggregated complex containing GRP-78/BiP prior to their degradation by the pre-Golgi degradative pathway.
HLA class II molecules are membrane proteins which are assembled in the endoplasmic reticulum shortly after synthesis of the alpha and beta and invariant chain (Ii) monomers. DR beta chains, in the absence of DR alpha, are rapidly and completely degraded by the pre-Golgi degradative pathway. Here we have examined those factors which target DR beta chains for degradation in a DR alpha deficient cell line, 9.22.3. The DR beta monomers in 9.22.3 were initially incorporated into a proteinaceous complex containing BiP. With time, the DR beta complexes were further aggregated. In wild type cells, which can assemble DR alpha-beta dimers, the secondary phase of aggregation of DR beta was not seen. Additional evidence that aggregation of DR beta in 9.22.3 cells was progressive was that a more mature form of DR beta was found exclusively in the largest DR beta complexes. Furthermore, the most highly aggregated DR beta chains were degraded more rapidly than bulk DR beta chains. These data suggest that DR beta aggregates are intermediates in the pre-Golgi pathway of DR beta degradation. They further suggest that formation of large DR beta aggregates is a proximal event to DR beta degradation. We conclude that DR beta chains are targeted for degradation as a consequence of a change of state, coincident with their aggregation into slow forming, high molecular weight complexes.
Department of Pediatrics, University of Washington, Seattle 98195.
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D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006056:Golgi Apparatus / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D018832:Molecular Chaperones / Q000378:metabolism*; D011485:Protein Binding
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006684:HLA-DR Antigens; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones