Abstract
During T cell development, assembly of the mutisubunit T cell receptor (TCR) complex is regulated by the differential stability of newly synthesized TCRalpha molecules, having a half-life of approximately 20 min in immature CD4+CD8+ thymocytes compared with >75 min in mature T cells. The molecular basis for TCRalpha instability in CD4+CD8+ thymocytes is unknown but has been postulated to involve abnormalities in N-glycan processing and calnexin assembly as perturbation of these pathways markedly destabilizes TCRalpha proteins in all other T cell types examined. Here, we compared the processing of TCRalpha glycoproteins and their assembly with calnexin and calreticulin chaperones in CD4+CD8+ thymocytes and splenic T cells. These studies show that TCRalpha glycoproteins synthesized in CD4+CD8+ thymocytes were processed in a similar manner as those made in splenic T cells and that TCRalpha proteins stably associated with calnexin in both cell types. Interestingly, however, TCRalpha association with the calnexin-related molecule calreticulin was decreased in CD4+CD8+ thymocytes compared with splenic T cells. Finally, TCRalpha degradation in CD4+CD8+ thymocytes was impaired by inhibitors of proteasome activity, which was correlated with stabilization of calnexin.TCRalpha complexes. These data demonstrate that calnexin association is not sufficient to protect TCRalpha proteins from rapid degradation in CD4+CD8+ thymocytes, suggesting that additional components of the quality control system of the endoplasmic reticulum operate to ensure the proper folding of nascent TCRalpha glycoproteins.
Highlights
Calnexin Association Is Not Sufficient to Protect T Cell Receptor ␣ Proteins from Rapid Degradation in CD4؉CD8؉ Thymocytes*
Our data demonstrate that T cell receptor (TCR)␣ glycoproteins are processed in a similar manner in both cell types, with Glc residues being removed from TCR␣ proteins before their assembly with CD3 components in CD4ϩCD8ϩ thymocytes, as previously reported for splenic T cells
TCR␣ molecules were stably associated with calnexin in both cell types, but interestingly, calreticulin1⁄7TCR␣ associations were decreased in CD4ϩCD8ϩ thymocytes relative to splenic T cells
Summary
Vol 273, No 37, Issue of September 11, pp. 23674 –23680, 1998 Printed in U.S.A. Calnexin Association Is Not Sufficient to Protect T Cell Receptor ␣ Proteins from Rapid Degradation in CD4؉CD8؉ Thymocytes*. TCR␣ degradation in CD4؉CD8؉ thymocytes was impaired by inhibitors of proteasome activity, which was correlated with stabilization of calnexin1⁄7TCR␣ complexes These data demonstrate that calnexin association is not sufficient to protect TCR␣ proteins from rapid degradation in CD4؉CD8؉ thymocytes, suggesting that additional components of the quality control system of the endoplasmic reticulum operate to ensure the proper folding of nascent TCR␣ glycoproteins. Persistence of Glc residues on N-glycans precludes formation of calnexin1⁄7 TCR␣ complexes and results in the rapid degradation of TCR␣ proteins [15, 16, 18], occurring much faster than is typically observed for TCR␣ protein turnover under conditions where glycan processing is unperturbed These results are specific in that the stability of related TCR glycoproteins is unaffected by impaired glucosidase activity and the failure to assemble with calnexin [15, 17,18,19]. To enhance our understanding of the molecular basis for the limited survival of newly synthesized TCR␣ proteins in immature CD4ϩCD8ϩ thymocytes, we undertook the present study to examine and compare the processing of TCR␣ glycoproteins and their assembly with lectin-like chaperones in CD4ϩCD8ϩ thymocytes and splenic T cells
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