Dimmeler S, Haendeler J, Sause A, Zeiher A M
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.
Cell Growth Differ. 1998 May;9(5):415-22.
Activation of the cysteine protease caspases, which are homologous to the product of Caenorhabditis elegans cell-death gene ced 3, is required to mediate APO-1/Fas-induced apoptosis. We report here that nitric oxide (NO) released by exogenous NO donors, as well as NO endogenously derived by transfection with the inducible NO synthase, substantially suppresses APO-1/Fas-triggered cell death of Jurkat cells. The inhibitory NO effect was independent of cGMP, because 8-bromo-cGMP did not influence APO-1/Fas-mediated apoptosis. In contrast, NO interferes with the APO-1/Fas-induced stimulation of caspases. NO inhibits the proteolytic cleavage of caspase-3 (CPP32) into its active subunits, thereby suppressing caspase-3 activity. In addition, NO potently inhibits apoptosis induction by overexpresssion of the death domain protein FADD or the immediate downstream target caspase-8. These results suggest that NO modulates the proteolytic cascade upstream of caspase-3. Indeed, NO specifically S-nitrosylates caspase-8 and caspase-1 and thereby may prevent activation of the proteolytic cascade. The NO-mediated increase in the resistance toward induction of apoptosis may play a major role in mediating immune responses, as well as in the pathogenesis of autoimmune diseases.
半胱氨酸蛋白酶（胱天蛋白酶）的激活是介导APO-1/Fas诱导的细胞凋亡所必需的，该蛋白酶与秀丽隐杆线虫细胞死亡基因ced 3的产物同源。我们在此报告，外源性一氧化氮（NO）供体释放的NO以及通过转染诱导型一氧化氮合酶内源性产生的NO，能显著抑制Jurkat细胞中APO-1/Fas触发的细胞死亡。NO的抑制作用不依赖于环磷酸鸟苷（cGMP），因为8-溴-cGMP不影响APO-1/Fas介导的细胞凋亡。相反，NO干扰APO-1/Fas诱导的胱天蛋白酶激活。NO抑制胱天蛋白酶-3（CPP32）蛋白水解切割成其活性亚基，从而抑制胱天蛋白酶-3的活性。此外，NO能有效抑制因死亡结构域蛋白FADD或其直接下游靶点胱天蛋白酶-8过表达所诱导的细胞凋亡。这些结果表明，NO调节胱天蛋白酶-3上游的蛋白水解级联反应。事实上，NO特异性地使胱天蛋白酶-8和胱天蛋白酶-1亚硝基化，从而可能阻止蛋白水解级联反应的激活。NO介导的对细胞凋亡诱导抗性的增加可能在介导免疫反应以及自身免疫性疾病的发病机制中起主要作用。
