Team
Team manager: Chapat Clément
Presentation
The proteome is defined as the set of proteins produced by a cell, and varies considerably from one cell to another depending on its type, function, the tissue in which it resides and the signals it receives from its environment. A cell’s homeostasis is therefore intimately orchestrated by the composition and quality of its proteome, and depends on how its transcriptome is handled by the translation apparatus.
During translation, the ribosome, assisted by transfer RNAs (tRNAs), decodes messenger RNAs (mRNAs) to produce the corresponding proteins. The term “translatome” has been proposed to define the population of mRNAs directly involved in translation at any given time. It is now becoming clear that a significant level of gene expression regulation is happening at the level of protein translation and that dysregulation of these protein translation regulatory mechanisms is promoting cancer. In our laboratory, we conduct fundamental research into various key molecular processes that shape the translatome of human cells. Furthermore, we study very novel mechanism of dysregulating the translatome in cancer cells.
Project
The post-transcriptional regulations of the human translatome represent a new terra incognita to be explored in biology. Post-transcriptional silencing mechanisms modulate mRNA stability and translation, contributing to the rapid and flexible control of protein synthesis. This phenomenon mainly relies on the repressive activity of various mRNA-driven machineries which can be mobilized by microRNAs, RNA-binding proteins and mRNA modifications. Recent data showed that silencing machineries have a selective activity based on the codon composition of the targeted mRNA. Why and how these machineries promote a bidirectional modulation of mRNA translation and decay based on codon usage remains an outstanding question. With this in mind, our research at the Centre for Integrative Biology of Toulouse aims to investigate the mechanisms that link the translation apparatus with mRNA silencing machineries, and how this interaction drives cell-fate decisions. In particular, we seek to set up an integrated experimental framework to measure the impact of ribosome-targeting by mRNA decay factors on translational landscapes. Altogether, our results open a fascinating window into our understanding of how a physical intimacy between mRNA silencing machineries and translation apparatus shapes the ever-changing swarm of proteins that differs from cell to cell.
– Moch C, Zou L, Pythoud N, Fillon E, Bourgeois G, Graille M, Carapito C, Chapat C*. The YTHDF1-3 proteins are bidirectionally influenced by the codon content of their mRNA targets. BioRxiv. November 20, 2023. doi.org/10.1101/2023.11.20.565808
– Oudart M, Avila-Gutierrez K, Moch C, Dossi E, Milior G, Boulay AC, Gaudey M, Moulard J, Lombard B, Loew D, Bemelmans AP, Rouach N, Chapat C, Cohen-Salmon M. The ribosome-associated protein RACK1 represses Kir4.1 translation in astrocytes and influences neuronal activity. Cell Reports. 2023 May 30;42(5):112456.
– Zou L, Moch C, Graille M, Chapat C*. The SARS-CoV-2 protein NSP2 impairs the silencing capacity of the human 4EHP-GIGYF2 complex. iScience. 2022 July 15;25(7):104646. doi: 10.1016/j.isci.2022.104646 (*corresponding author)
– Zhang X, Chapat C, Wang P, Choi JH, Li Q, Luo J, Wiebe S, Kim SH, Robichaud N, Karam IF, Dai D, Hackett AP, Lin R, Alain T, Yang L, Jafarnejad SM, Sonenberg N. microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP. Molecular Cell. 2021 Mar 18. 81(6):1187-1199.e5.
– Hazra D, Chapat C, Graille M. m6A mRNA Destiny: Chained to the rhYTHm by the YTH-Containing Proteins. Genes. 2019, 10(1), 49
– Jafarnejad SM*, Chapat C*, Matta-Camacho E, Gelbart IA, Hesketh GG, Arguello M, Garzia A, Kim SH, Attig J, Shapiro M, Morita M, Khoutorsky A, Alain T, Gkogkas CG, Stern-Ginossar N, Tuschl T, Gingras AC, Duchaine TF, Sonenberg N. Translational control of ERK signaling through miRNA/4EHP-directed silencing. Elife. 2018 Feb 7;7. pii: e35034. doi: 10.7554 (#co-first authors)
– -Garzia A, Jafarnejad SM, Meyer C, Chapat C, Gogakos T, Morozov P, Amiri M, Shapiro M, Molina H, Tuschl T, Sonenberg N. The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature Communications. 2017;8:16056.
– Chapat C*, Chettab K, Simonet P, Wang P, De La Grange P, Le Romancer M, Corbo L. Alternative splicing of CNOT7 diversifies CCR4-NOT functions. Nucleic Acids Research. 2017 Aug 21;45 (14):8508-8523. (*corresponding author)
– Chapat C*, Jafarnejad SM#, Matta-Camacho E, Hesketh GG, Gelbart IA, Attig J, Gkogkas CG, Alain T, Stern-Ginossar N, Fabian MR, Gingras AC, Duchaine TF, Sonenberg N. Cap-binding protein 4EHP effects translation silencing by microRNAs. Proc Natl Acad Sci USA. 2017 May 23;114(21):5425-5430.
