近日，美国德克萨斯大学西南医学中心W. Lee Kraus及其研究小组发现，核糖体ADP-核苷酸化抑制翻译并维持癌症中的蛋白质稳定。2021年7月26日，国际知名学术期刊《细胞》在线发表了这一成果。

研究人员表明，细胞膜NAD⁺合成通过调节翻译和维持蛋白质平衡在卵巢癌中起着重要作用。NMNAT-2是一种细胞膜NAD⁺合成酶，其表达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，该酶将核糖体蛋白单(ADP-核糖基)化(MARylation)。NMNAT-2或PARP-16的耗尽导致MARylation受到抑制，多聚体的联合增加，特定mRNA的翻译增强，其翻译的蛋白产物聚集，以及卵巢癌细胞的生长减少。

此外，核糖体蛋白的MARylation，如RPL24 d RPS6，通过稳定eIF6与核糖体的结合抑制多聚体的组装。总之，这些结果表明，核糖体MARylation通过微调蛋白质合成水平和防止有毒的蛋白质聚集来促进癌症中的蛋白质平衡。

据介绍，翻译的缺陷导致了蛋白质表达的变化，这些蛋白质可以作为癌症形成的驱动因素。

附：英文原文

Title: Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers

Author: Sridevi Challa, Beman R. Khulpateea, Tulip Nandu, Cristel V. Camacho, Keun W. Ryu, Hao Chen, Yan Peng, Jayanthi S. Lea, W. Lee Kraus

Issue&Volume: 2021-07-26

Abstract: Defects in translation lead to changes in the expression of proteins that can serveas drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation andmaintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalyticactivity 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 inhibitionof MARylation, increased polysome association and enhanced translation of specificmRNAs, aggregation of their translated protein products, and reduced growth of ovariancancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 d RPS6,inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively,our results demonstrate that ribosome MARylation promotes protein homeostasis in cancersby fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.

DOI: 10.1016/j.cell.2021.07.005

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00831-X