Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

被引:7
|
作者
Inoue, Masanori [1 ,2 ]
Miyahara, Hiroaki [3 ]
Shiraishi, Hiroshi [1 ]
Shimizu, Nobuyuki [1 ]
Tsumori, Mika [2 ]
Kiyota, Kyoko [2 ]
Maeda, Miwako [2 ]
Umeda, Ryohei [4 ]
Ishitani, Tohru [5 ]
Hanada, Reiko [4 ]
Ihara, Kenji [2 ]
Hanada, Toshikatsu [1 ]
机构
[1] Oita Univ, Dept Cell Biol, Fac Med, Yufu, Oita 8795593, Japan
[2] Oita Univ, Dept Pediat, Fac Med, Yufu, Oita 8795593, Japan
[3] Aichi Med Univ, Inst Med Sci Aging, Dept Neuropathol, Nagakute, Aichi 4801195, Japan
[4] Oita Univ, Dept Neurophysiol, Fac Med, Yufu, Oita 8795593, Japan
[5] Osaka Univ, Res Inst Microbial Dis, Dept Homeostat Regulat, Div Cellular & Mol Biol, Osaka 5650871, Japan
基金
日本学术振兴会;
关键词
L-FABP GENE; CELL-DEATH; RECESSIVE MUTATIONS; EXPRESSION; LIVER; IDENTIFICATION; MECHANISMS; PATHWAYS; TYPE-1; LC3;
D O I
10.1038/s41598-021-87879-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:13
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