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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doaj-735bf8722fc14b5aa74a3a1a7b470b4c2021-04-18T11:37:07ZengNature Publishing GroupScientific Reports2045-23222021-04-0111111310.1038/s41598-021-87879-4Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafishMasanori Inoue0Hiroaki Miyahara1Hiroshi Shiraishi2Nobuyuki Shimizu3Mika Tsumori4Kyoko Kiyota5Miwako Maeda6Ryohei Umeda7Tohru Ishitani8Reiko Hanada9Kenji Ihara10Toshikatsu Hanada11Department of Cell Biology, Oita University Faculty of MedicineDepartment of Neuropathology, Institute for Medical Science of Aging, Aichi Medical UniversityDepartment of Cell Biology, Oita University Faculty of MedicineDepartment of Cell Biology, Oita University Faculty of MedicineDepartment of Pediatrics, Oita University Faculty of MedicineDepartment of Pediatrics, Oita University Faculty of MedicineDepartment of Pediatrics, Oita University Faculty of MedicineDepartment of Neurophysiology, Oita University Faculty of MedicineDivision of Cellular and Molecular Biology, Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Neurophysiology, Oita University Faculty of MedicineDepartment of Pediatrics, Oita University Faculty of MedicineDepartment of Cell Biology, Oita University Faculty of MedicineAbstract 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.https://doi.org/10.1038/s41598-021-87879-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-04-01 |
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. |
url |
https://doi.org/10.1038/s41598-021-87879-4 |
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