Pham C T, Ley T J
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8627-32. doi: 10.1073/pnas.96.15.8627.
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that has been implicated in the processing of granzymes, which are neutral serine proteases exclusively expressed in the granules of activated cytotoxic lymphocytes. In this report, we show that cytotoxic lymphocytes derived from DPPI-/- mice contain normal amounts of granzymes A and B, but these molecules retain their prodipeptide domains and are inactive. Cytotoxic assays with DPPI-/- effector cells reveal severe defects in the induction of target cell apoptosis (as measured by [(125)I]UdR release) at both early and late time points; this defect is comparable to that detected in perforin-/- or granzyme A-/- x B-/- cytotoxic lymphocytes. DPPI therefore plays an essential role in the in vivo processing and activation of granzymes A and B, which are required for cytotoxic lymphocyte granule-mediated apoptosis.
二肽基肽酶I(DPPI)是一种溶酶体半胱氨酸蛋白酶,与颗粒酶的加工过程有关,颗粒酶是仅在活化的细胞毒性淋巴细胞颗粒中表达的中性丝氨酸蛋白酶。在本报告中,我们表明,来自DPPI-/-小鼠的细胞毒性淋巴细胞含有正常量的颗粒酶A和B,但这些分子保留其前二肽结构域且无活性。用DPPI-/-效应细胞进行的细胞毒性试验显示,在早期和晚期时间点,靶细胞凋亡诱导(通过[(125)I]UdR释放测量)均存在严重缺陷;这种缺陷与在穿孔素-/-或颗粒酶A-/-x B-/-细胞毒性淋巴细胞中检测到的缺陷相当。因此,DPPI在颗粒酶A和B的体内加工和激活中起重要作用,而颗粒酶A和B是细胞毒性淋巴细胞颗粒介导的凋亡所必需的。