Leishmania mexicana metacaspase is a negative regulator of amastigote proliferation in mammalian cells
Leishmania mexicana metacaspase is a negative regulator of amastigote proliferation in mammalian cells
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DOI：
10.1038/cddis.2012.113
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发表时间：
2012-09-01
影响因子：
9
通讯作者：
Mottram, J. C.
中科院分区：
文献类型：
--
作者：
Castanys-Munoz, E.;Brown, E.;Mottram, J. C.
半胱天冬酶（metacaspase, MCAs）是半胱天冬酶家族的半胱氨酸肽酶，与植物、真菌和原生动物的细胞死亡过程有关。MCAs也被认为参与细胞周期控制、分化和聚集体的清除；它们是毒力因子。由于在许多生物体中存在多个MCA基因或基因操作的限制，解剖MCA的功能变得复杂。我们在这里描述了在原生动物寄生虫墨西哥利什曼原虫中产生的MCA基因缺失突变体（Delta MCA），这使我们能够解剖寄生虫的单个MCA基因在细胞生长和细胞死亡中的作用。在体外巨噬细胞感染和小鼠体内，δ mca寄生虫都能以原鞭毛体形式存活，并正常分化为无尾鞭毛体形式。Delta mca promastigotes对药物miltefosine和H2O2等细胞死亡诱导剂的反应与野生型（WT） promastigotes相似，这表明MCAs在L. mexicana细胞死亡中不具有caspase样的作用。在巨噬细胞和小鼠中，Delta mca无尾线虫的复制速度明显快于WT无尾线虫，但在体外无菌培养中则不然。我们提出利什曼原虫MCA作为无尾线虫增殖的负调节因子，从而起到平衡细胞生长和细胞死亡的作用。细胞死亡与疾病（2012）3,e385；doi: 10.1038 / cddis.2012.113;2012年9月6日在线发布
Metacaspases (MCAs) are caspase family cysteine peptidases that have been implicated in cell death processes in plants, fungi and protozoa. MCAs have also been suggested to be involved in cell cycle control, differentiation and clearance of aggregates; they are virulence factors. Dissecting the function of MCAs has been complicated by the presence in many organisms of multiple MCA genes or limitations on genetic manipulation. We describe here the creation of a MCA gene-deletion mutant (Delta mca) in the protozoan parasite Leishmania mexicana, which has allowed us to dissect the role of the parasite's single MCA gene in cell growth and cell death. Delta mca parasites are viable as promastigotes, and differentiate normally to the amastigote form both in in vitro macrophages infection and in mice. Delta mca promastigotes respond to cell death inducers such as the drug miltefosine and H2O2 similarly to wild-type (WT) promastigotes, suggesting that MCAs do not have a caspase-like role in execution of L. mexicana cell death. Delta mca amastigotes replicated significantly faster than WT amastigotes in macrophages and in mice, but not as axenic culture in vitro. We propose that the Leishmania MCA acts as a negative regulator of amastigote proliferation, thereby acting to balance cell growth and cell death. Cell Death and Disease (2012) 3, e385; doi:10.1038/cddis.2012.113; published online 6 September 2012