2. Academic Validation
  3. Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis

Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis

  • EMBO J. 2024 Jul 31. doi: 10.1038/s44318-024-00184-4.
Caroline Wathieu 1 2,  Arnaud Lavergne 3,  Xinyi Xu 1 2,  Marion Rolot 4,  Ivan Nemazanyy 5,  Kateryna Shostak 1 2,  Najla El Hachem 1 6,  Chloé Maurizy 1 2,  Charlotte Leemans 1 6,  Pierre Close 1 6 7,  Laurent Nguyen 1 7 8,  Christophe Desmet 1 9,  Sylvia Tielens # 1 2,  Benjamin G Dewals # 4,  Alain Chariot # 10 11 12
Affiliations

Affiliations

  • 1 Interdisciplinary Cluster for Applied Genoproteomics, Liege, Belgium.
  • 2 Laboratory of Cancer Biology, GIGA, University of Liege, Liege, Belgium.
  • 3 GIGA Genomics Platform, University of Liege, Liege, Belgium.
  • 4 Laboratory of Immunology-Vaccinology, Fundamental and Applied Research in Animals and Health (FARAH), University of Liege, Liege, Belgium.
  • 5 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
  • 6 Laboratory of Cancer Signaling, GIGA, University of Liege, Liege, Belgium.
  • 7 WELBIO department, WEL Research Institute, avenue Pasteur, 6, 1300, Wavre, Belgium.
  • 8 Laboratory of Molecular Regulation of Neurogenesis, University of Liege, Liege, Belgium.
  • 9 Laboratory of Cellular and Molecular Immunology, University of Liege, Liege, GIGA-I3, Belgium.
  • 10 Interdisciplinary Cluster for Applied Genoproteomics, Liege, Belgium. Alain.chariot@uliege.be.
  • 11 Laboratory of Cancer Biology, GIGA, University of Liege, Liege, Belgium. Alain.chariot@uliege.be.
  • 12 WELBIO department, WEL Research Institute, avenue Pasteur, 6, 1300, Wavre, Belgium. Alain.chariot@uliege.be.
  • # Contributed equally.
PMID: 39085648 DOI: 10.1038/s44318-024-00184-4
Abstract

Intestinal tuft cells are critical for anti-helminth Parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying Enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth Infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic Enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 Inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth Infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.

Keywords

ATF4; Tuft Cells; mTORC1; tRNA Modifications.

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