Deletion of mitochondrial associated ubiquitin fold modifier protein Ufm1 in Leishmania donovani results in loss of β-oxidation of fatty acids and blocks cell division in the amastigote stage.
Deletion of mitochondrial associated ubiquitin fold modifier protein Ufm1 in Leishmania donovani results in loss of β-oxidation of fatty acids and blocks cell division in the amastigote stage.
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DOI：
10.1111/j.1365-2958.2012.08183.x
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发表时间：
2012-10
影响因子：
3.6
通讯作者：
Nakhasi HL
中科院分区：
文献类型：
--
作者：
Gannavaram S;Connelly PS;Daniels MP;Duncan R;Salotra P;Nakhasi HL
最近，我们描述了杜氏利什曼原虫中泛素折叠修饰子1（Ufm 1）的存在及其结合途径。我们证明了Ufm 1与蛋白质如线粒体三功能蛋白（MTP）的结合，该蛋白质催化L. donovani。为了阐明Ufm 1介导的修饰的生物学作用，我们制备了L. Donovani Ufm 1无效突变体（Ufm 1 −/−）。Ufm 1的缺失以及随后Ufm 1与MTP结合的缺失导致乙酰辅酶A减少，乙酰辅酶A是Ufm 1 −/−无鞭毛体阶段β-氧化的终产物。Ufm 1 −/−突变体在体外和离体人类巨噬细胞中无鞭毛体阶段的存活率降低。通过再表达野生型Ufm 1并伴随乙酰辅酶A的诱导而恢复了这种存活，但通过再表达不可缀合的Ufm 1而没有恢复，这表明Ufm 1缀合和β-氧化的本质。Ufm 1 −/−寄生虫的细胞周期分析和超微结构研究都证实了Ufm 1在无鞭毛体生长中的作用。通过减少存活率进一步证实了在人巨噬细胞中无鞭毛体体外生长的缺陷。因此，这些研究表明Ufm 1在利什曼原虫发病机制中的重要性，对其他生物体的影响更大，并进一步提供了测试Ufm 1 −/−寄生虫作为药物和疫苗靶点的机会。
Recently, we described the existence of the ubiquitin fold modifier1 (Ufm1) and its conjugation pathway in Leishmania donovani. We demonstrated the conjugation of Ufm1 to proteins such as mitochondrial trifunctional protein (MTP) that catalyzes β-oxidation of fatty acids in L. donovani. To elucidate the biological roles of the Ufm1-mediated modifications, we made an L. donovani Ufm1 null mutant (Ufm1−/−). Loss of Ufm1 and consequently absence of Ufm1 conjugation with MTP resulted in diminished acetyl-CoA, the end product of the β-oxidation in the Ufm1−/− amastigote stage. The Ufm1−/− mutants showed reduced survival in the amastigote stage in vitro and ex vivo in human macrophages. This survival was restored by re-expression of wild type Ufm1 with concomitant induction of acetyl-CoA but not by re-expressing the non-conjugatable Ufm1, indicating the essential nature of Ufm1 conjugation and β-oxidation. Both cell cycle analysis and ultrastructural studies of Ufm1−/− parasites confirmed the role of Ufm1 in amastigote growth. The defect in vitro growth of amstigotes in human macrophages was further substantiated by reduced survival. Therefore, these studies suggest the importance of Ufm1 in Leishmania pathogenesis with larger impact on other organisms and further provide an opportunity to test Ufm1−/− parasites as drug and vaccine targets.
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