Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy

Matthew J. Justice, Irina Bronova, Kelly S. Schweitzer, Christophe Poirier, Janice S. Blum, Evgeny V. Berdyshev, Irina Petrache

Research output: Contribution to journalArticle

5 Scopus citations

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 +/ 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.

Original languageEnglish (US)
Pages (from-to)596-606
Number of pages11
JournalJournal of Lipid Research
Volume59
Issue number4
DOIs
StatePublished - 2018

Keywords

  • Endothelial cells
  • Lung
  • Lysosomal nutrient-sensing complex
  • Lysosome
  • Mammalian target of rapamycin
  • Membrane
  • Sphingolipids
  • Sphingosine

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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