Article (Scientific journals)
Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.
Chen, Dawei; Nemazanyy, Ivan; Peulen, Olivier et al.
2022In EMBO Journal, p. 109353
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Keywords :
Elp3; mTORC2; macrophage polarization; mitochondrial translation; tRNA modifications; Neuroscience (all); Molecular Biology; Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Neuroscience
Abstract :
[en] Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.
Disciplines :
Immunology & infectious disease
Author, co-author :
Chen, Dawei  ;  Université de Liège - ULiège > GIGA
Nemazanyy, Ivan ;  Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France
Peulen, Olivier  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie dans le domaine des sciences médicales et biomédicales
Shostak, Kateryna ;  Université de Liège - ULiège > GIGA > GIGA Stem Cells - Medical Chemistry
Xu, Xinyi ;  Université de Liège - ULiège > GIGA
Tang, Seng Chuan ;  Université de Liège - ULiège > GIGA > GIGA Stem Cells - Medical Chemistry
Wathieu, Caroline  ;  Université de Liège - ULiège > GIGA
Turchetto, Silvia ;  Université de Liège - ULiège > GIGA
Tielens, Sylvia ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Nguyen, Laurent  ;  Université de Liège - ULiège > GIGA > GIGA Stem Cells
Close, Pierre  ;  Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavres, Belgium
Desmet, Christophe  ;  Université de Liège - ULiège > GIGA > GIGA I3 - Cellular and Molecular Immunology
Klein, Sebastian ;  Institute for Pathology-University Hospital Cologne, Köln, Germany
Florin, Alexandra;  Institute for Pathology-University Hospital Cologne, Köln, Germany
Büttner, Reinhard ;  Institute for Pathology-University Hospital Cologne, Köln, Germany
Petrellis, Georgios  ;  Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Dewals, Benjamin G  ;  Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Chariot, Alain  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de chimie clinique ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavres, Belgium
More authors (8 more) Less
Language :
English
Title :
Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.
Publication date :
03 August 2022
Journal title :
EMBO Journal
ISSN :
0261-4189
eISSN :
1460-2075
Publisher :
John Wiley and Sons Inc, England
Pages :
e109353
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Stichting tegen Kanker [BE]
Centre for Dengue Research, University of Sri Jayewardenepura
Walloon excellence in life sciences and biotechnology
Funding text :
The authors are grateful to the GIGA Imaging platform for the FACS analyses. They also thank Dr. Zhang from NIBIO (Olso, Norway) for providing us R scripts on RNA‐seq and proteomics analysis. This work was supported by grants from WELBIO (WELBIO‐CR‐2019C‐02R), FNRS/TELEVIE, the Belgian Foundation against Cancer (FBC/2020/1323), the University of Liege (ARC UBICOREAR) and by the Leon Fredericq Foundation (Faculty of Medicine, CHU of Liege). PC and AC are Senior Research Associate and Research Director at the FNRS, respectively.
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since 11 September 2022

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