A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice
A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice
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DOI：
10.1007/s10495-009-0394-y
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发表时间：
2009-10-01
期刊：
影响因子：
7.2
通讯作者：
Jacotot, Etienne
中科院分区：
文献类型：
--
作者：
Brabant, Magali;Baux, Ludwig;Jacotot, Etienne
登革病毒属于黄病毒科，是引起人类出血热的病原体。登革病毒感染尤其通过小膜（M）蛋白的表达触发细胞凋亡。使用分离的线粒体，我们发现，合成的肽含有C-末端部分的M胞外域引起线粒体相关的线粒体膜透化（MMP）事件。这些事件包括基质肿胀和线粒体跨膜电位（Delta I-m）的消散。蛋白M黄病毒序列比对和螺旋轮预测揭示了保守的带电残基分布。此外，当与细胞穿透HIV-1达特肽转导结构域（Tat-PTD）结合时，该序列触发与Δ I-m损失和细胞色素c释放相关的半胱天冬酶依赖性细胞死亡。突变的方法耦合到分离的线粒体上的功能筛选导致在分离的线粒体上选择含有9个残基的蛋白M衍生序列，其具有有效的MMP诱导特性。由与9聚体实体连接的Tat-PTD组成的嵌合肽触发MMP和细胞死亡。最后，这种嵌合肽的局部给药诱导异种移植前列腺PC 3肿瘤在免疫受损小鼠中的生长抑制，并显著提高动物存活率。总之，这些发现支持使用病毒基因组作为有价值的来源来发现可能导致开发新的抗癌化合物的靶向序列的概念。
Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (Delta I-m). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with Delta I-m loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.