A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases.
A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases.
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DOI：
10.1038/cddis.2010.2
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发表时间：
2010
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
最近对恶性疟原虫程序性细胞死亡(PCD)特征的几项新发现为揭示抗疟疾治疗的新靶点提供了可能性。采用细胞分析、流式细胞术和荧光显微镜相结合的方法，我们检测了氯喹(CQ)和星形孢子素(ST)诱导的寄生虫的线粒体失调、半胱氨酸蛋白酶激活和DNA原位断裂等特征。使用泛caspase抑制剂z-Val-Ala-Asp-fmk(ZVAD)和线粒体外膜通透性(MOMP)抑制剂4-羟基他莫昔芬，能够表征CQ诱导的将半胱氨酸蛋白酶激活与下游线粒体失调、放大的蛋白酶活性和DNA片段化联系起来的新途径。只有在高浓度(μM)的CQ时才能观察到PCD特征。一种新的合成香豆素标记的氯喹(CM-CQ)的使用表明，这些特征可能与药物定位的浓度依赖的差异有关。通过进一步使用半胱氨酸蛋白酶抑制剂z-Asp-Glu-Val-Asp-fmk(ZDEVD)、z-Phe-Ala-fmk(ZfA)、z-Phe-Phe-fmk(Zff)、z-Leu-fmk(ZL11)、E64d和CA-074，我们能够将CA家族半胱氨酸蛋白酶与CQ介导的PCD联系起来。最后，对两个CQ抗性寄生虫株7G8和K1的CQ诱导表明，这些寄生虫中存在PCD特征，其程度小于3D7。化学逆转剂维拉帕米的使用表明，寄生虫的消化液泡参与了CQ诱导的PCD。
Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD.
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影响因子：
1.5
作者：
Farias, SL;Gazarini, ML;Garcia, CRS
通讯作者：
Garcia, CRS
影响因子：
3.2
作者：
Alexander, MD;Burkart, MD;La Clair, JJ
通讯作者：
La Clair, JJ
影响因子：
3.5
作者：
Morkuniene, R;Jekabsone, A;Borutaite, V
通讯作者：
Borutaite, V
影响因子：
16
作者：
Madeo, F;Herker, E;Fröhlich, KU
通讯作者：
Fröhlich, KU
DOI：
10.1016/s0006-291x(89)80065-8
发表时间：
1989-01-31
影响因子：
3.1
作者：
MCGOWAN, EB;BECKER, E;DETWILER, TC
通讯作者：
DETWILER, TC