THE ALPHA-CHAIN OF THE T-CELL ANTIGEN RECEPTOR IS DEGRADED IN THE CYTOSOL

To reach the cell surface, the T cell receptor for antigen (TCR)-CD3 c omplex must assemble in the endoplasmic reticulum (ER), where single s ubunits are retained and degraded. However, the exact location of brea kdown and the mechanism and proteases involved in destruction of free subunits have remained elusive. We show that degradation of the TCR al pha chain is impaired in the presence of lactacystin and carboxybenzyl -leucyl-leucyl-leucinal, two inhibitors for proteasomal proteolysis. W e identified breakdown intermediates that were either soluble, cytosol ic, and devoid of N-linked glycans, or membrane-associated and partial ly deglycosylated by cytosolic N-glycanase. Protease protection experi ments showed a cytosolic disposition of these membrane-associated inte rmediates. Combined, these results argue for a cytosolic degradation r oute of the TCR alpha chain involving dislocation from the ER, followe d by cytosolic deglycosylation and proteolysis by the proteasome.