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
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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