A big BiP on the radar screen

759 he discovery of immunoglob-ulin heavy chain binding protein (BiP) in antibody-producing cells (Morrison and Scharff, 1975; Haas and Wabl, 1984) had researchers trying to assign an immune function to it. In one theory, BiP was thought to regulate allelic exclusion of heavy and light chain genes (Wabl and Steinberg, 1982). Part of the theory assumed that BiP neutralized a proposed heavy chain toxicity. If a cell was making heavy chains improperly from both alleles, then there would not be enough BiP to go around and the cells would die and be eliminated from the B lymphocyte pool.) had been working with pre–B cell hybridomas that only produced heavy chains yet suffered no toxic effect, so he questioned the toxicity idea. He started by making a BiP antibody. The unexpected endpoint would be the competitive area of chaperone biology. T A hybridoma expert, Kearney, along with graduate student David Bole, immunized rats with the mouse BiP-heavy chain complex and made a mono-clonal antibody that recognized both free BiP and BiP bound to its target molecule. The team, eventually joined by postdoc Linda Hendershot, used the antibody to follow BiP in two cell lines—a nonsecretor and a secretor—to see how it interacted with Ig molecules at different stages of completion. In the cell line that produced only nonsecreted Ig heavy chains, BiP was stably associated with the heavy chains. But in the cell line that secreted completed Ig complexes of two light and two heavy chains, BiP dissociated from the Ig complex once heavy chains became associated with light chains (Bole et al., 1986). Furthermore, in the secreting line, BiP stayed associated with all of the Ig intermediates until the last light chain was added. They concluded that BiP prevented the premature secretion of incomplete Ig molecules. The group also localized BiP to the rough ER. This, along with the lab's unpublished observations that BiP was showing up in every imaginable cell type and in all species tested (even lobsters with no immune system), catapulted the immunologists into a raging cell biology debate about protein transport from the ER. Did receptors carry proteins forward, or was there bulk flow with a retention mechanism for unfolded proteins? " Here, " says Hendershot, now at St. Jude's Children's Hospital (Memphis, TN), " we had an ER protein that associated with every intermediate, but not with the completely assembled complex, " thus bolstering the …