Gil-Torregrosa B C, Raúl Castaño A, Del Val M
Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, Madrid, Spain.
J Exp Med. 1998 Sep 21;188(6):1105-16. doi: 10.1084/jem.188.6.1105.
Classical antigen presentation by major histocompatibility complex class I molecules involves cytosolic processing of endogenously synthesized antigens by proteasomes and translocation of processed peptides into the endoplasmic reticulum (ER) by transporters associated with antigen presentation (TAP). Alternative pathways for processing of endogenous antigens, generally involving the ER, have been suggested but not fully proved. We analyzed the potential for class I presentation of proteolytic maturation of secretory antigens in the exocytic pathway. We found that hepatitis B (HB) virus secretory core protein HBe can efficiently deliver COOH-terminally located antigenic peptides for endogenous class I loading in the absence of TAP. Antigen presentation to specific 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 maturation and a necessary processing step occur in the Golgi or post-Golgi compartment. Antigen presentation is independent of proteasome activity, but inhibitors of the trans-Golgi network resident protease furin inhibit both HBe maturation and antigen presentation. These results define a new antigen processing pathway located in the secretory route, with a central role for proteolytic maturation mediated by the subtilisin protease family member furin as an efficient source for antigen presentation.
主要组织相容性复合体I类分子的经典抗原呈递涉及蛋白酶体对内源合成抗原的胞质加工，以及与抗原呈递相关的转运体（TAP）将加工后的肽转运至内质网（ER）。已提出了加工内源抗原的替代途径，通常涉及内质网，但尚未得到充分证实。我们分析了分泌途径中分泌性抗原蛋白水解成熟的I类呈递潜力。我们发现，在没有TAP的情况下，乙型肝炎（HB）病毒分泌核心蛋白HBe可以有效地将位于COOH末端的抗原肽递送至内源性I类负载。向特异性细胞毒性T淋巴细胞的抗原呈递与COOH末端的蛋白质成熟相关，因为HBe通过分泌途径的成熟和转运修饰会改变抗原呈递。成熟和必要的加工步骤均发生在高尔基体或高尔基体后区室。抗原呈递独立于蛋白酶体活性，但反式高尔基体网络驻留蛋白酶弗林蛋白酶的抑制剂会抑制HBe成熟和抗原呈递。这些结果定义了一种位于分泌途径中的新抗原加工途径，枯草杆菌蛋白酶家族成员弗林蛋白酶介导的蛋白水解成熟作为抗原呈递的有效来源发挥着核心作用。
