@article {313,
	title = {A disease-causing isoleucyl-tRNA synthetase variant leads to altered protein complex formation and cellular stress response.},
	journal = {J Biol Chem},
	volume = {302},
	year = {2026},
	month = {2026 Jan 23},
	pages = {111196},
	abstract = {<p>Aminoacyl-tRNA synthetases are key enzymes in protein synthesis, as they catalyze the attachment of amino acids to their designated, cognate tRNAs. As such, mutations in aminoacyl-tRNA synthetases are associated with severe diseases, such as neurodevelopmental disorders. Many of these mutations occur in the catalytically active site or tRNA-binding domains; however, others can affect domains associated with multisynthetase complex formation. Here, we investigate a disease-causing mutation in the unique-I domain of isoleucyl-tRNA synthetase (IARS1, IleRS), which mediates IleRS interactions within the multisynthetase complex. Interestingly, levels of the resulting protein were severely reduced in comparison to wt IleRS. While bulk protein synthesis and cell proliferation were not affected, the integrated stress response signaling pathway was altered. This change was exacerbated in low-glucose medium, suggesting that mutant cells could respond differently to cellular stress. Our study hints at a possible underlying disease mechanism, where catalytic activity might not be affected but instead complex formation and protein stability.</p>},
	issn = {1083-351X},
	doi = {10.1016/j.jbc.2026.111196},
	author = {Gao, Han and Tennakoon, Rasangi and Ara{\'u}jo, Felicia Pais and Miller, Jolie M and Nyandwi, Samuel Protais and Shi, Qingyu and Padilla-Mart{\'\i}nez, Juan Pablo and Peng, Hui and Cui, Haissi}
}
