Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy
Imipramine
Lysosomal nutrient-sensing complex
Endothelial cells
Mice, Transgenic
QD415-436
Biochemistry
lung
Mice
03 medical and health sciences
Sphingosine
Autophagy
Animals
Humans
Enzyme Inhibitors
RNA, Small Interfering
Lung
membrane
Cells, Cultured
Mice, Knockout
Sphingolipids
0303 health sciences
Mammalian target of rapamycin
sphingolipids
sphingosine
Membrane
Lysosome
endothelial cells
Mice, Inbred C57BL
Sphingomyelin Phosphodiesterase
Multiprotein Complexes
lysosome
Lysosomes
Signal Transduction
DOI:
10.1194/jlr.m080242
Publication Date:
2018-01-29T16:05:55Z
AUTHORS (7)
ABSTRACT
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+/- haploinsufficiency 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.
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CITATIONS (31)
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