MLF1 is a proapoptotic antagonist of HOP complex-mediated survival.
MLF1 is a proapoptotic antagonist of HOP complex-mediated survival.
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DOI：
10.1016/j.bbamcr.2017.01.016
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Yi Sun;Jyh-Rong Chao;Wu Xu;Alan Pourpak;K. Boyd;S. Moshiach;Guo-Yan Qi;Amina Fu;Hua-Rong Shao-Hua-Rong-S
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文献类型：
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作者：
Yi Sun;Jyh-Rong Chao;Wu Xu;Alan Pourpak;K. Boyd;S. Moshiach;Guo-Yan Qi;Amina Fu;Hua-Rong Shao-Hua-Rong-S
在 HAX1/HtrA2-OMI/PARL (HOP) 线粒体蛋白复合物中，在将两种蛋白酶募集到线粒体内膜蛋白 HAX1（HS1 相关蛋白 X-1）上后，菱形蛋白酶 PARL 裂解并激活丝氨酸蛋白酶 HtrA2/OMI，从而产生抗凋亡信号。在这里，我们报告了人类白血病相关髓细胞白血病因子 1 (MLF1) 对 HOP 复合物的负调控。我们证明 MLF1 在物理和功能上与 HAX1 和 HtrA2 相关。 MLF1 与 HAX1 和 HtrA2 相互作用的增强会从 HOP 复合物中取代 HtrA2，并抑制 HtrA2 裂解和激活，导致细胞凋亡。相反，过表达的HAX1会中和MLF1的作用并抑制MLF1诱导的细胞凋亡。重要的是，Mlf1缺失逆转了B细胞和T细胞淋巴细胞减少症，并显着改善了Hax1−/−小鼠中观察到的进行性纹状体和小脑神经变性，与Hax1−/−动物相比，Mlf1−/−/Hax1−/−动物的寿命延长了一倍。总的来说，这些数据表明 MLF1 作为促凋亡拮抗剂，与 HOP 线粒体复合物相互作用来调节细胞存活。
In theHAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1−/−mice, with a doubling of the lifespan of Mlf1−/−/Hax1−/−animals compared to Hax1−/−animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.