NOVEL ASPECTS OF DEGRADATION OF T-CELL RECEPTOR SUBUNITS FROM THE ENDOPLASMIC-RETICULUM (ER) IN T-CELLS - IMPORTANCE OF OLIGOSACCHARIDE PROCESSING, UBIQUITINATION, AND PROTEASOME-DEPENDENT REMOVAL FROM ER MEMBRANES

Expression of the T cell antigen receptor (TCR) on the surface of thym ocytes and mature T cells is dependent on the assembly of receptor sub units into TCRs in the endoplasmic reticulum (ER) and their successful traversal of the secretory pathway to the plasma membrane. TCR subuni ts that fail to exit the ER for the Golgi complex are degraded by nonl ysosomal processes that have been referred to as ''ER degradation''. T he molecular basis for the loss of the TCR CD3-delta and TCR-alpha sub units from the ER was investigated in lymphocytes. For CD3-delta, we d escribe a process leading to its degradation that includes trimming of mannose residues from asparagine-linked (N-linked) oligosaccharides, generation of ubiquitinated membrane-bound intermediates, and proteaso me-dependent removal from the ER membrane. When either mannosidase act ivity or the catalytic activity of proteasomes was inhibited, loss of CD3-delta was markedly curtailed and CD3-delta remained membrane bound in a complex with CD3-epsilon. TCR-alpha was also found to be degrade d in a proteasome-dependent manner with ubiquitinated intermediates. H owever, no evidence of a role for mannosidases was found for TCR-alpha , and significant retrograde movement through the ER membrane took pla ce even when proteasome function was inhibited. These findings provide new insights into mechanisms employed to regulate levels of TCRs, and underscore that cells use multiple mechanisms to target proteins from the ER to the cytosol for degradation.