Elp3-flox Mouse

Elp3, also known as Elongator protein 3 or Kat9, is the catalytic subunit of the Elongator complex. It functions as an acetyltransferase and a tRNA-modifying enzyme, modifying the wobble uridine base U34 in cytosolic tRNAs. Elp3 is involved in multiple pathways such as mTORC2 activation, Wnt signaling, and is important for processes like macrophage polarization, cell metabolism, and tumorigenesis. Genetic models, especially KO/CKO mouse models, have been crucial in understanding its functions [1-6, 8].

In myeloid cells of mice, Elp3 expression is downregulated by M1-activating signals, limiting pro-inflammatory cytokines production via FoxO1 phosphorylation and attenuating experimental colitis. In contrast, M2-activating signals upregulate its expression, and M2 macrophage polarization-linked metabolic reprogramming depends on Elp3. Elp3 also promotes mTORC2 activation by codon-dependent translation of its activator Ric8b and further promotes Wnt-driven tumor initiation in the intestine [1]. In another study, Elp3 knockdown in mice diminished glycolysis and glutaminolysis, retarded cell proliferation and xenograft growth by downregulating c-Myc, as it stabilizes c-Myc in an acetyltransferase-independent manner [2]. Loss of epithelial Elp3 in mouse intestine blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis, as it is essential for immature tuft cell generation and IL-13-dependent induction of glycolytic enzymes [3]. In hematopoietic system of mice, loss of Elp3 causes bone marrow failure, activates a p53-dependent checkpoint, and can lead to development of p53-mutated leukemia/lymphoma [4].

In conclusion, Elp3 plays essential roles in macrophage polarization, cell metabolism, tumorigenesis, and hematopoiesis. Mouse models with Elp3 KO/CKO have provided valuable insights into its functions in these processes and associated disease conditions such as colitis, cancer, and bone marrow failure, helping to understand the underlying mechanisms and potentially identify new therapeutic targets.