An essential role for the Leishmania major metacaspase in cell cycle progression
An essential role for the Leishmania major metacaspase in cell cycle progression
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DOI：
10.1038/sj.cdd.4402232
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Mottram, J. C.
中科院分区：
文献类型：
--
作者：
Ambit, A.;Fasel, N.;Mottram, J. C.
Metacaspases（MCAs）是caspase的远亲同源物，在酵母和植物细胞的程序性死亡中发挥重要作用，但在寄生原虫中的功能尚不清楚。硕大利什曼原虫MCA基因（LmjMCA）在活跃复制的无鞭毛体和前环前鞭毛体中表达，但在后环前鞭毛体中表达水平较低。LmjMCA在间期细胞中的整个细胞中具有点状分布，但在细胞器分离时集中在动质体（线粒体DNA）中。LmjMCA还在有丝分裂期间易位到细胞核，在那里它与有丝分裂纺锤体缔合。LmjMCA在前鞭毛体中的过表达导致严重的生长迟缓和倍性变化，这是由于动质体分离和核分裂的缺陷以及胞质分裂的损伤。不能产生LmjMCA无效突变体，并且在遗传操作以从附加体表达LmjMCA之后，唯一可行的突变体是以生理水平表达LmjMCA的那些。这些数据表明，在L。主要活性LmjMCA对于细胞核和动质体的正确分离是必不可少的，其功能可能独立于程序性细胞死亡，并且LmjMCA的量是至关重要的。哺乳动物中没有MCAs使得这种酶成为对抗原生动物寄生虫的潜在药物靶标。
Metacaspases (MCAs) are distant orthologues of caspases and have been proposed to play a role in programmed cell death in yeast and plants, but little is known about their function in parasitic protozoa. The MCA gene of Leishmania major (LmjMCA) is expressed in actively replicating amastigotes and procyclic promastigotes, but at a lower level in metacyclic promastigotes. LmjMCA has a punctate distribution throughout the cell in interphase cells, but becomes concentrated in the kinetoplast (mitochondrial DNA) at the time of the organelle's segregation. LmjMCA also translocates to the nucleus during mitosis, where it associates with the mitotic spindle. Overexpression of LmjMCA in promastigotes leads to a severe growth retardation and changes in ploidy, due to defects in kinetoplast segregation and nuclear division and an impairment of cytokinesis. LmjMCA null mutants could not be generated and following genetic manipulation to express LmjMCA from an episome, the only mutants that were viable were those expressing LmjMCA at physiological levels. Together these data suggest that in L. major active LmjMCA is essential for the correct segregation of the nucleus and kinetoplast, functions that could be independent of programmed cell death, and that the amount of LmjMCA is crucial. The absence of MCAs from mammals makes the enzyme a potential drug target against protozoan parasites.