mRNA decay pre-complex assembly drives timely cell-state transitions during differentiation

Hideyuki Komori; Geeta Rastogi; John Paul Bugay; Hua Luo; Sichun Lin; Stephane Angers; Craig A Smibert; Howard D Lipshitz; Cheng-Yu Lee

doi:10.1016/j.celrep.2024.115138

mRNA decay pre-complex assembly drives timely cell-state transitions during differentiation

Cell Rep. 2024 Dec 30;44(1):115138. doi: 10.1016/j.celrep.2024.115138. Online ahead of print.

Authors

Hideyuki Komori¹, Geeta Rastogi¹, John Paul Bugay², Hua Luo³, Sichun Lin⁴, Stephane Angers⁵, Craig A Smibert⁶, Howard D Lipshitz³, Cheng-Yu Lee⁷

Affiliations

¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.
⁴ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada.
⁷ 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; Division of Genetic Medicine, Department of Internal Medicine and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: leecheng@umich.edu.

PMID: 39739530
DOI: 10.1016/j.celrep.2024.115138

Abstract

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.

Keywords: Brat; CP: Developmental biology; CP: Molecular biology; Drosophila; Usp5; cell state transitions; deadenylase complexes; differentiation; mRNA decay; maternal mRNAs; neuroblast.