The cellular proteome determines the functional state of cells and is often skewed to direct pathological conditions. Autophagy shapes cellular proteomes primarily through lysosomal degradation of either damaged or unnecessary proteins. Here, we show that autophagy directs the senescence-specific translatome to fuel inflammation by coupling selective protein degradation with alternative splicing. RNA splicing is significantly altered during senescence, some of which surprisingly depend on autophagy, including exon 5 skipping of the translation regulator EIF4H. Systematic translatome profiling indicates that this event is key to the translational bias toward inflammation in senescence. Autophagy promotes these changes by selectively degrading the splicing regulator splicing factor proline and glutamine rich (SFPQ) via the autophagy receptor NBR1. These autophagy-centric inflammatory controls appear to be conserved during human tissue aging and cancer. Our work highlights the role of autophagy in the on-demand functional remodeling of cellular proteomes as well as the crosstalk between autophagy, alternative splicing, and inflammatory translation.

中文翻译：

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自噬依赖性剪接控制在衰老过程中将翻译引导至炎症


细胞蛋白质组决定细胞的功能状态，并且通常偏向于直接的病理条件。自噬主要通过溶酶体降解受损或不必要的蛋白质来塑造细胞蛋白质组。在这里，我们表明自噬通过将选择性蛋白质降解与选择性剪接相结合来指导衰老特异性翻译组来促进炎症。RNA 剪接在衰老过程中发生显著改变，其中一些令人惊讶地依赖于自噬，包括翻译调节因子 EIF4H 的外显子 5 跳跃。系统的翻译组分析表明，该事件是衰老时对炎症的翻译偏倚的关键。自噬通过自噬受体 NBR1 选择性降解剪接调节因子脯氨酸和富含谷氨酰胺 （SFPQ） 来促进这些变化。这些以自噬为中心的炎症控制在人体组织衰老和癌症期间似乎是保守的。我们的工作强调了自噬在细胞蛋白质组按需功能重塑中的作用，以及自噬、选择性剪接和炎症翻译之间的串扰。