Sadoul R, Fernandez P A, Quiquerez A L, Martinou I, Maki M, Schröter M, Becherer J D, Irmler M, Tschopp J, Martinou J C
Geneva Biomedical Research Institute, 14 chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
EMBO J. 1996 Aug 1;15(15):3845-52.
Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin-1beta converting enzyme (ICE)/Ced-3-like cysteine protease, indicating involvement of this class of proteases in the cell death programme. Here we demonstrate that the proteolytic activities of the proteasome are also essential in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors, including the highly selective inhibitor lactacystin, not only prolonged survival of NGF-deprived neurons but also prevented processing of poly(ADP-ribose) polymerase which is known to be cleaved by an ICE/Ced-3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstream of proteases of the ICE/Ced-3 family. This order of events was confirmed in macrophages where lactacystin inhibited the proteolytic activation of precursor ICE and the subsequent generation of active interleukin-1beta.
交感神经元在缺乏神经生长因子（NGF）时会经历程序性细胞死亡（PCD）。神经元的PCD被白细胞介素-1β转换酶（ICE）/Ced-3样半胱氨酸蛋白酶抑制剂所阻断，这表明这类蛋白酶参与了细胞死亡程序。在此我们证明蛋白酶体的蛋白水解活性在神经元的PCD中也至关重要。纳摩尔浓度的几种蛋白酶体抑制剂，包括高度选择性抑制剂乳胞素，不仅延长了缺乏NGF的神经元的存活时间，还阻止了聚（ADP-核糖）聚合酶的加工处理，已知在PCD过程中聚（ADP-核糖）聚合酶会被ICE/Ced-3家族成员切割。这些结果表明蛋白酶体是神经元PCD的关键调节因子，并且在这个过程中，它参与ICE/Ced-3家族蛋白酶的上游作用。在巨噬细胞中证实了这种事件顺序，在巨噬细胞中乳胞素抑制了前体ICE的蛋白水解激活以及随后活性白细胞介素-1β的产生。
