Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD⁺ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD⁺ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.

翻译缺陷会导致蛋白质表达发生变化，这些蛋白质可以作为癌症形成的驱动因素。在这里，我们表明细胞溶质 NAD ⁺合成通过调节翻译和维持蛋白质稳态在卵巢癌中发挥重要作用。NMNAT-2 的表达，一种细胞溶质 NAD ⁺合酶在卵巢癌中高度上调。NMNAT-2 支持单（ADP-核糖基）转移酶 (MART) PARP-16 的催化活性，该酶单（ADP-核糖基）化（MARylate）核糖体蛋白。NMNAT-2 或 PARP-16 的消耗导致抑制 MARylation、增加多核糖体结合和增强特定 mRNA 的翻译、其翻译的蛋白质产物的聚集以及卵巢癌细胞的生长减少。此外，核糖体蛋白（如 RPL24 和 RPS6）的 MARylation 通过稳定 eIF6 与核糖体的结合来抑制多核糖体组装。总的来说，我们的研究结果表明，核糖体 MARylation 通过微调蛋白质合成水平和防止有毒蛋白质聚集来促进癌症中的蛋白质稳态。