Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
Cell Death Dis. 2022 Feb 2;13(2):101. doi: 10.1038/s41419-022-04532-2.
Hippo signaling is a conserved mechanism for controlling organ growth. Increasing evidence suggests that Hippo signaling is modulated by various cellular factors for normal development and tumorigenesis. Hence, identification of these factors is pivotal for understanding the mechanism for the regulation of Hippo signaling. Drosophila Mnat9 is a putative N-acetyltransferase that is required for cell survival by affecting JNK signaling. Here we show that Mnat9 is involved in the negative regulation of Hippo signaling. RNAi knockdown of Mnat9 in the eye disc suppresses the rough eye phenotype of overexpressing Crumbs (Crb), an upstream factor of the Hippo pathway. Conversely, Mnat9 RNAi enhances the eye phenotype caused by overexpressing Expanded (Ex) or Warts (Wts) that acts downstream to Crb. Similar genetic interactions between Mnat9 and Hippo pathway genes are found in the wing. The reduced wing phenotype of Mnat9 RNAi is suppressed by overexpression of Yorkie (Yki), while it is suppressed by knockdown of Hippo upstream factors like Ex, Merlin, or Kibra. Mnat9 co-immunoprecipitates with Mer, implying their function in a protein complex. Furthermore, Mnat9 overexpression together with Hpo knockdown causes tumorous overgrowth in the abdomen. Our data suggest that Mnat9 is required for organ growth and can induce tumorous growth by negatively regulating the Hippo signaling pathway.
Hippo 信号通路是一种保守的机制，用于控制器官生长。越来越多的证据表明，Hippo 信号通路受到各种细胞因子的调节，以维持正常的发育和肿瘤发生。因此，鉴定这些因子对于理解 Hippo 信号通路的调控机制至关重要。果蝇 Mnat9 是一种假定的 N-乙酰转移酶，通过影响 JNK 信号通路来维持细胞存活。在这里，我们发现 Mnat9 参与 Hippo 信号通路的负调控。在眼盘中敲低 Mnat9 的 RNAi 抑制了 Hippo 通路上游因子 Crumbs (Crb)过表达导致的粗糙眼表型。相反，Mnat9 RNAi 增强了 Crb 下游的 Expanded (Ex) 或 Warts (Wts) 过表达引起的眼部表型。在翅膀中也发现了 Mnat9 和 Hippo 通路基因之间的类似遗传相互作用。Mnat9 RNAi 的翅膀表型缺陷被 Yki (Yki) 的过表达所抑制，而 Hippo 上游因子如 Ex、Merlin 或 Kibra 的敲低则会抑制 Mnat9 RNAi 的翅膀表型。Mnat9 与 Mer 共免疫沉淀，暗示它们在蛋白质复合物中发挥作用。此外，Mnat9 过表达与 Hpo 敲低一起导致腹部肿瘤性过度生长。我们的数据表明，Mnat9 是器官生长所必需的，并且可以通过负调控 Hippo 信号通路来诱导肿瘤性生长。
