Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

Abstract Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes inf...

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Autores principales:	Masanori Inoue, Hiroaki Miyahara, Hiroshi Shiraishi, Nobuyuki Shimizu, Mika Tsumori, Kyoko Kiyota, Miwako Maeda, Ryohei Umeda, Tohru Ishitani, Reiko Hanada, Kenji Ihara, Toshikatsu Hanada
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/735bf8722fc14b5aa74a3a1a7b470b4c
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spelling	oai:doaj.org-article:735bf8722fc14b5aa74a3a1a7b470b4c2021-12-02T14:26:12ZLeucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish10.1038/s41598-021-87879-42045-2322https://doaj.org/article/735bf8722fc14b5aa74a3a1a7b470b4c2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87879-4https://doaj.org/toc/2045-2322Abstract Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb −/− ) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb −/− zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb −/− zebrafish. Indeed, excessive autophagy activation was observed in larsb −/− zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.Masanori InoueHiroaki MiyaharaHiroshi ShiraishiNobuyuki ShimizuMika TsumoriKyoko KiyotaMiwako MaedaRyohei UmedaTohru IshitaniReiko HanadaKenji IharaToshikatsu HanadaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masanori Inoue Hiroaki Miyahara Hiroshi Shiraishi Nobuyuki Shimizu Mika Tsumori Kyoko Kiyota Miwako Maeda Ryohei Umeda Tohru Ishitani Reiko Hanada Kenji Ihara Toshikatsu Hanada Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
description	Abstract Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb −/− ) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb −/− zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb −/− zebrafish. Indeed, excessive autophagy activation was observed in larsb −/− zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.
format	article
author	Masanori Inoue Hiroaki Miyahara Hiroshi Shiraishi Nobuyuki Shimizu Mika Tsumori Kyoko Kiyota Miwako Maeda Ryohei Umeda Tohru Ishitani Reiko Hanada Kenji Ihara Toshikatsu Hanada
author_facet	Masanori Inoue Hiroaki Miyahara Hiroshi Shiraishi Nobuyuki Shimizu Mika Tsumori Kyoko Kiyota Miwako Maeda Ryohei Umeda Tohru Ishitani Reiko Hanada Kenji Ihara Toshikatsu Hanada
author_sort	Masanori Inoue
title	Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
title_short	Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
title_full	Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
title_fullStr	Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
title_full_unstemmed	Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish
title_sort	leucyl-trna synthetase deficiency systemically induces excessive autophagy in zebrafish
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/735bf8722fc14b5aa74a3a1a7b470b4c
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Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

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