Chen, Dawei ORCID: 0000-0002-2541-4512, Nemazanyy, Ivan, Peulen, Olivier ORCID: 0000-0002-6933-0134, Shostak, Kateryna, Xu, Xinyi, Tang, Seng Chuan, Wathieu, Caroline, Turchetto, Silvia, Tielens, Sylvia, Nguyen, Laurent, Close, Pierre, Desmet, Christophe, Klein, Sebastian, Florin, Alexandra, Buttner, Reinhard, Petrellis, Georgios, Dewals, Benjamin and Chariot, Alain (2022). Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization. Embo J., 41 (18). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chen, DaweiUNSPECIFIEDorcid.org/0000-0002-2541-4512UNSPECIFIED
Nemazanyy, IvanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peulen, OlivierUNSPECIFIEDorcid.org/0000-0002-6933-0134UNSPECIFIED
Shostak, KaterynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, XinyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, Seng ChuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wathieu, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Turchetto, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tielens, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen, LaurentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Close, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Desmet, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buttner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petrellis, GeorgiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dewals, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chariot, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-686054
DOI: 10.15252/embj.2021109353
Journal or Publication Title: Embo J.
Volume: 41
Number: 18
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRANSFER-RNA MODIFICATION; TRANSCRIPTION FACTOR; COMPLEXMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68605

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