Beyond a platform protein for the degradosome assembly: The Apoptosis-Inducing Factor as an efficient nuclease involved in chromatinolysis.
Beyond a platform protein for the degradosome assembly: The Apoptosis-Inducing Factor as an efficient nuclease involved in chromatinolysis.
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DOI：
10.1093/pnasnexus/pgac312
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发表时间：
2023-02
期刊：
影响因子：
--
通讯作者：
Ferreira, Patricia
中科院分区：
文献类型：
--
作者：
Novo, Nerea;Romero-Tamayo, Silvia;Marcuello, Carlos;Boneta, Sergio;Blasco-Machin, Irene;Velazquez-Campoy, Adrian;Villanueva, Raquel;Moreno-Loshuertos, Raquel;Lostao, Anabel;Medina, Milagros;Ferreira, Patricia
凋亡诱导因子（AIF）是一种兼职黄酶，参与健康细胞中线粒体呼吸复合物的组装，但也能引发DNA切割和旁咽下。在凋亡刺激下，AIF从线粒体重新分布到细胞核，在细胞核中与其他蛋白质如内切酶CypA和组蛋白H2AX结合，被认为组织了一个dna降解体复合物。在这项工作中，我们为该复合体的分子组装以及其蛋白质组分之间的协同作用提供了证据，以将基因组DNA降解成大片段。我们还发现AIF具有在Mg2+或Ca2+存在下刺激的核酸酶活性。这种活性使得AIF可以单独或与CypA协同有效地降解基因组DNA。最后，我们确定了AIF中的TopIB和DEK基序与其核酸酶活性有关。这些新发现首次指出AIF是一种能够消化死亡细胞中细胞核dsDNA的核酸酶，提高了我们对其在促进细胞凋亡中的作用的理解，并为开发新的治疗策略开辟了道路。
The Apoptosis-Inducing Factor (AIF) is a moonlighting flavoenzyme involved in the assembly of mitochondrial respiratory complexes in healthy cells, but also able to trigger DNA cleavage and parthanatos. Upon apoptotic-stimuli, AIF redistributes from the mitochondria to the nucleus, where upon association with other proteins such as endonuclease CypA and histone H2AX, it is proposed to organize a DNA–degradosome complex. In this work, we provide evidence for the molecular assembly of this complex as well as for the cooperative effects among its protein components to degrade genomic DNA into large fragments. We have also uncovered that AIF has nuclease activity that is stimulated in the presence of either Mg2+ or Ca2+. Such activity allows AIF by itself and in cooperation with CypA to efficiently degrade genomic DNA. Finally, we have identified TopIB and DEK motifs in AIF as responsible for its nuclease activity. These new findings point, for the first time, to AIF as a nuclease able to digest nuclear dsDNA in dying cells, improving our understanding of its role in promoting apoptosis and opening paths for the development of new therapeutic strategies.
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