Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy
Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy
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DOI：
10.1194/jlr.m080242
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发表时间：
2018-04-01
影响因子：
6.5
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
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作者：
Justice, Matthew J.;Bronova, Irina;Petrache, Irina
溶酶体神经酰胺生成酶酸性鞘磷脂酶（ASM）在各种应激作用下的活化与细胞死亡和自噬有关。我们开始研究基线ASM活性在维持溶酶体生理功能中的作用，重点研究溶酶体营养感应复合体（LYNUS），这是一种溶酶体膜锚定的多蛋白复合体，包括哺乳动物雷帕霉素靶蛋白（mTOR）和转录因子EB （TFEB）。用丙咪嗪或人肺细胞鞘磷脂二酯酶1(SMPD1) siRNA抑制ASM，或通过转基因小鼠肺SMPD1（+/-）单倍不足，可显著降低mtor和P70-S6激酶（Thr 389）的磷酸化，并以与其激活一致的模式修饰TFEB。抑制基线ASM活性显著增加自噬并保留降解电位。神经鞘脂代谢产物的脉冲标记显示，ASM抑制显著降低神经酰胺水解水平的鞘氨醇（Sph）和Sph-1-磷酸（S1P）水平。这些发现表明，ASM可以维持生理性mTOR信号传导，抑制自噬，并与Sph和/或S1P参与溶酶体功能的控制。
Activation of the lysosomal ceramide-producing enzyme, acid sphingomyelinase (ASM), by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on the lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB). ASM inhibition with imipramine or sphingomyelin phosphodiesterase 1 (SMPD1) siRNA in human lung cells, or by transgenic Smpd1(+/-) haplo-insufficiency of mouse lungs, markedly reduced mTOR-and P70-S6 kinase (Thr 389)-phosphorylation and modified TFEB in a pattern consistent with its activation. Inhibition of baseline ASM activity significantly increased autophagy with preserved degradative potential. Pulse labeling of sphingolipid metabolites revealed that ASM inhibition markedly decreased sphingosine (Sph) and Sph-1-phosphate (S1P) levels at the level of ceramide hydrolysis. These findings suggest that ASM functions to maintain physiological mTOR signaling and inhibit autophagy and implicate Sph and/or S1P in the control of lysosomal function.