Department of Medicine, Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
Elife. 2018 Oct 16;7:e38621. doi: 10.7554/eLife.38621.
CD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported that CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (Putzbach et al., 2017). We now report expression of full-length CD95L mRNA itself is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) which is required for the toxicity and processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.
CD95/Fas 配体与死亡受体 CD95 结合，诱导敏感细胞凋亡。我们之前报道过，CD95L mRNA 富含序列，当这些序列被转化为 si/shRNAs 时，通过靶向关键生存基因杀死所有癌细胞（Putzbach 等人，2017 年）。我们现在报告全长 CD95L mRNA 本身对细胞具有高度毒性，并诱导类似的细胞死亡形式。我们证明，源自 CD95L 的小（s）RNAs 被装载到 RNA 诱导的沉默复合物（RISC）中，这对于毒性和将 CD95L mRNA 加工成 sRNAs 是必需的，而 Dicer 和 Drosha 都不参与。我们提供的证据表明，除了 CD95L 转基因外，许多参与调节蛋白质翻译的内源性蛋白质编码基因，特别是在 miRNA 水平较低的情况下，可以被加工成 sRNAs 并装载到 RISC 中，这表明涉及 RNAi 的细胞命运调节的新水平。
