Xue Maoguang, Cong Fei, Zheng Wanling, Xu Ruoqing, Liu Xiaoyu, Bao Hongcun, Sung Ying Ying, Xi Yongmei, He Feng, Ma Jun, Yang Xiaohang, Ge Wanzhong
Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Cell Death Discov. 2023 Aug 5;9(1):288. doi: 10.1038/s41420-023-01587-8.
Regulation of protein translation initiation is tightly associated with cell growth and survival. Here, we identify Paip1, the Drosophila homolog of the translation initiation factor PAIP1, and analyze its role during development. Through genetic analysis, we find that loss of Paip1 causes reduced protein translation and pupal lethality. Furthermore, tissue specific knockdown of Paip1 results in apoptotic cell death in the wing imaginal disc. Paip1 depletion leads to increased proteotoxic stress and activation of the integrated stress response (ISR) pathway. Mechanistically, we show that loss of Paip1 promotes phosphorylation of eIF2α via the kinase PERK, leading to apoptotic cell death. Moreover, Paip1 depletion upregulates the transcription factor gene Xrp1, which contributes to apoptotic cell death and eIF2α phosphorylation. We further show that loss of Paip1 leads to an increase in Xrp1 translation mediated by its 5'UTR. These findings uncover a novel mechanism that links translation impairment to tissue homeostasis and establish a role of ISR activation and Xrp1 in promoting cell death.
蛋白质翻译起始的调控与细胞生长和存活密切相关。在此，我们鉴定了翻译起始因子PAIP1的果蝇同源物Paip1，并分析了其在发育过程中的作用。通过遗传分析，我们发现Paip1的缺失导致蛋白质翻译减少和蛹期致死。此外，组织特异性敲低Paip1会导致翅成虫盘的凋亡性细胞死亡。Paip1的缺失导致蛋白毒性应激增加和综合应激反应（ISR）途径的激活。从机制上讲，我们表明Paip1的缺失通过激酶PERK促进eIF2α的磷酸化，导致凋亡性细胞死亡。此外，Paip1的缺失上调转录因子基因Xrp1，这有助于凋亡性细胞死亡和eIF2α磷酸化。我们进一步表明，Paip1的缺失导致由其5'UTR介导的Xrp1翻译增加。这些发现揭示了一种将翻译损伤与组织稳态联系起来的新机制，并确立了ISR激活和Xrp1在促进细胞死亡中的作用。
