MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I VIRAL-ANTIGEN PROCESSING IN THE SECRETORY PATHWAY DEFINED BY THE TRANS-GOLGI NETWORK PROTEASE FURIN

Classical antigen presentation by major histocompatibility complex cla ss I molecules involves cytosolic processing of endogenously synthesiz ed antigens by proteasomes and translocation of processed peptides int o the endoplasmic reticulum (ER) by transporters associated with antig en presentation (TAP). Alternative pathways for processing of endogeno us antigens, generally involving the ER, have been suggested but not f ully proved. We analyzed the potential for class I presentation of pro teolytic maturation of secretory antigens in the exocytic pathway. We found that hepatitis B (HB) virus secretory core protein HBe can effic iently deliver COOH-terminally located antigenic peptides for endogeno us class I loading in the absence of TAP. Antigen presentation to spec ific cytotoxic T lymphocytes correlates with protein maturation at the COOH terminus, since modification of maturation and transport of HBe through the secretory pathway alters antigen presentation. Both matura tion and a necessary processing step occur in the Golgi or post-Golgi compartment. Antigen presentation is independent of proteasome activit y, but inhibitors of the trans-Golgi network resident protease furin i nhibit both HBe maturation and antigen presentation. These results def ine a new antigen processing pathway located in the secretory route, w ith a central role for proteolytic maturation mediated by the subtilis in protease family member furin as an efficient source for antigen pre sentation.