Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cell. 2018 Jun 28;174(1):187-201.e12. doi: 10.1016/j.cell.2018.04.017. Epub 2018 May 17.
Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3' end, triggered by the mitochondrial intermembrane space 3'-to-5' exoribonuclease PNPT1, released during MOMP. PNPT1 knockdown inhibits apoptotic RNA decay and reduces apoptosis, while ectopic expression of PNPT1, but not an RNase-deficient mutant, increases RNA decay and cell death. The 3' end of PNPT1 substrates thread through a narrow channel. Many non-poly(A) ncRNAs contain 3'-secondary structures or bind proteins that may block PNPT1 activity. Indeed, mutations that disrupt the 3'-stem-loop of a decay-resistant ncRNA render the transcript susceptible, while adding a 3'-stem-loop to an mRNA prevents its decay. Thus, PNPT1 release from mitochondria during MOMP initiates apoptotic decay of RNAs lacking 3'-structures.
广泛的 mRNA 降解，凋亡的一个未被认识的特征，增强细胞死亡，并依赖于线粒体外膜通透性（MOMP）、TUTases 和 DIS3L2。哪些 RNA 被降解以及起始降解的事件尚不清楚。在这里，我们显示了广泛的 mRNA 和 poly(A) 非编码（nc）RNA 在 3' 端的降解，这是由线粒体间空间 3'-5' 外切核糖核酸酶 PNPT1 触发的，该酶在 MOMP 期间释放。PNPT1 敲低抑制凋亡 RNA 降解并减少细胞凋亡，而外源性表达 PNPT1（而不是缺乏 RNase 的突变体）增加 RNA 降解和细胞死亡。PNPT1 底物的 3' 端穿过一个狭窄的通道。许多非多聚（A）ncRNA 含有 3'-二级结构或结合可能阻断 PNPT1 活性的蛋白质。事实上，破坏抗降解 ncRNA 的 3'-茎环结构的突变使其易受影响，而在 mRNA 上添加 3'-茎环则阻止其降解。因此，MOMP 期间线粒体中 PNPT1 的释放引发了缺乏 3'-结构的凋亡性 RNA 降解。
