Komori Hideyuki, Rastogi Geeta, Bugay John Paul, Luo Hua, Lin Sichun, Angers Stephane, Smibert Craig A, Lipshitz Howard D, Lee Cheng-Yu
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cell Rep. 2025 Jan 28;44(1):115138. doi: 10.1016/j.celrep.2024.115138. Epub 2024 Dec 30.
Complexes that control mRNA stability and translation promote timely cell-state transitions during differentiation by ensuring appropriate expression patterns of key developmental regulators. The Drosophila RNA-binding protein brain tumor (Brat) promotes the degradation of target transcripts during the maternal-to-zygotic transition in syncytial embryos and uncommitted intermediate neural progenitors (immature INPs). We identify ubiquitin-specific protease 5 (Usp5) as a candidate Brat interactor essential for the degradation of Brat target mRNAs. Usp5 promotes the formation of the Brat-deadenylase pre-complex in mitotic neural stem cells (neuroblasts) by facilitating Brat interactions with the scaffolding components of deadenylase complexes. The adaptor protein Miranda binds the RNA-binding domain of Brat, limiting its ability to bind target mRNAs in mitotic neuroblasts. Cortical displacement of Miranda activates Brat-deadenylase complex activity in immature INPs. We propose that the assembly of an enzymatically inactive and RNA-binding-deficient pre-complex poises mRNA degradation machineries for rapid activation, driving timely developmental transitions.
控制mRNA稳定性和翻译的复合物通过确保关键发育调节因子的适当表达模式，在分化过程中促进及时的细胞状态转变。果蝇RNA结合蛋白脑肿瘤（Brat）在合胞体胚胎和未定型中间神经祖细胞（未成熟INP）的母源向合子转变过程中促进靶转录本的降解。我们确定泛素特异性蛋白酶5（Usp5）是Brat靶mRNA降解所必需的候选Brat相互作用蛋白。Usp5通过促进Brat与去腺苷酸化酶复合物的支架成分相互作用，促进有丝分裂神经干细胞（神经母细胞）中Brat-去腺苷酸化酶前复合物的形成。衔接蛋白米兰达（Miranda）结合Brat的RNA结合结构域，限制其在有丝分裂神经母细胞中结合靶mRNA的能力。米兰达在皮层的移位激活了未成熟INP中的Brat-去腺苷酸化酶复合物活性。我们提出，一种无酶活性且缺乏RNA结合能力的前复合物的组装使mRNA降解机制能够快速激活，从而推动及时的发育转变。
