Genome-Wide RNAi Screens Identify Genes Required for Ricin and PE Intoxications
Genome-Wide RNAi Screens Identify Genes Required for Ricin and PE Intoxications
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DOI：
10.1016/j.devcel.2011.06.014
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发表时间：
2011-08-16
影响因子：
11.8
通讯作者：
Bard, Frederic
中科院分区：
文献类型：
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作者：
Moreau, Dimitri;Kumar, Pankaj;Bard, Frederic
蓖麻毒素和假单胞菌外毒素（PE）等蛋白质毒素构成了重大的公共卫生挑战。这两种毒素依赖于宿主细胞机制进行内化，从内体到ER的逆行运输，以及易位到胞质溶胶。虽然这两种毒素遵循相似的细胞内途径，但它们在多大程度上依赖于相同的基因尚不清楚。在这里，我们进行了两个全基因组RNAi筛选，确定了中毒所需的基因，并证明了PE和蓖麻毒素之间的要求是惊人的不同，只有13%的重叠。然而，这两种毒素所需的因子都存在于从内体到ER的过程中，并且在形态学水平上，毒素共定位于多种结构中。有趣的是，蓖麻毒素，而不是PE，依赖于高尔基复合体的完整性和共定位显着与内侧高尔基体标记。我们的数据是一致的两个相互交织的途径，在多个点收敛和发散，并揭示了在哺乳动物细胞逆行膜贩运的复杂性。
Protein toxins such as Ricin and Pseudomonas exotoxin (PE) pose major public health challenges. Both toxins depend on host cell machinery for internalization, retrograde trafficking from endosomes to the ER, and translocation to cytosol. Although both toxins follow a similar intracellular route, it is unknown how much they rely on the same genes. Here we conducted two genome-wide RNAi screens identifying genes required for intoxication and demonstrating that requirements are strikingly different between PE and Ricin, with only 13% overlap. Yet factors required by both toxins are present from the endosomes to the ER, and, at the morphological level, the toxins colocalize in multiple structures. Interestingly, Ricin, but not PE, depends on Golgi complex integrity and colocalizes significantly with a medial Golgi marker. Our data are consistent with two intertwined pathways converging and diverging at multiple points and reveal the complexity of retrograde membrane trafficking in mammalian cells.