Inhibition of Acid Sphingomyelinase Disrupts LYNUS Signaling and Triggers Autophagy.

Inhibition of Acid Sphingomyelinase Disrupts LYNUS Signaling and Triggers Autophagy.

J Lipid Res. 2018 Jan 29;:

Authors: Justice MJ, Bronova I, Schweitzer KS, Poirier C, Blum JS, Berdyshev EV, Petrache I

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 lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes the mammalian target of rapamycin (mTOR) and the transcription factor EB (TFEB). ASM inhibition with imipramine or 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 and sphingosine-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 sphingosine and/or S1P in the control of lysosomal function.

PMID: 29378782 [PubMed - as supplied by publisher]

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