RapamycinFungusV1, Main, Exploration, bibRecord, 000573

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

Identifieur interne : 000573 ( Main/Exploration ); précédent : 000572; suivant : 000574

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

Auteurs : Matthew J. Justice [États-Unis] ; Irina Bronova [États-Unis] ; Kelly S. Schweitzer [États-Unis] ; Christophe Poirier [États-Unis] ; Janice S. Blum [États-Unis] ; Evgeny V. Berdyshev [États-Unis] ; Irina Petrache [États-Unis]

Source :

Journal of lipid research [ 1539-7262 ] ; 2018.

RBID : pubmed:29378782

Descripteurs français

KwdFr :
- Animaux (MeSH), Antienzymes (composition chimique), Antienzymes (pharmacologie), Autophagie (effets des médicaments et des substances chimiques), Cellules cultivées (MeSH), Complexes multiprotéiques (antagonistes et inhibiteurs), Complexes multiprotéiques (métabolisme), Humains (MeSH), Imipramine (composition chimique), Imipramine (pharmacologie), Lysosomes (effets des médicaments et des substances chimiques), Lysosomes (métabolisme), Petit ARN interférent (composition chimique), Petit ARN interférent (pharmacologie), Souris (MeSH), Souris de lignée C57BL (MeSH), Souris knockout (MeSH), Souris transgéniques (MeSH), Sphingomyeline phosphodiesterase (antagonistes et inhibiteurs), Sphingomyeline phosphodiesterase (déficit), Sphingomyeline phosphodiesterase (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques).
MESH :
- antagonistes et inhibiteurs : Complexes multiprotéiques, Sphingomyeline phosphodiesterase.
- composition chimique : Antienzymes, Imipramine, Petit ARN interférent.
- déficit : Sphingomyeline phosphodiesterase.
- effets des médicaments et des substances chimiques : Autophagie, Lysosomes, Transduction du signal.
- métabolisme : Complexes multiprotéiques, Lysosomes, Sphingomyeline phosphodiesterase.
- pharmacologie : Antienzymes, Imipramine, Petit ARN interférent.
- Animaux, Cellules cultivées, Humains, Souris, Souris de lignée C57BL, Souris knockout, Souris transgéniques.

English descriptors

KwdEn :
- Animals (MeSH), Autophagy (drug effects), Cells, Cultured (MeSH), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Humans (MeSH), Imipramine (chemistry), Imipramine (pharmacology), Lysosomes (drug effects), Lysosomes (metabolism), Mice (MeSH), Mice, Inbred C57BL (MeSH), Mice, Knockout (MeSH), Mice, Transgenic (MeSH), Multiprotein Complexes (antagonists & inhibitors), Multiprotein Complexes (metabolism), RNA, Small Interfering (chemistry), RNA, Small Interfering (pharmacology), Signal Transduction (drug effects), Sphingomyelin Phosphodiesterase (antagonists & inhibitors), Sphingomyelin Phosphodiesterase (deficiency), Sphingomyelin Phosphodiesterase (metabolism).
MESH :
- chemical , antagonists & inhibitors : Multiprotein Complexes, Sphingomyelin Phosphodiesterase.
- chemical , chemistry : Enzyme Inhibitors, Imipramine, RNA, Small Interfering.
- chemical , deficiency : Sphingomyelin Phosphodiesterase.
- drug effects : Autophagy, Lysosomes, Signal Transduction.
- metabolism : Lysosomes, Multiprotein Complexes, Sphingomyelin Phosphodiesterase.
- chemical , pharmacology : Enzyme Inhibitors, Imipramine, RNA, Small Interfering.
- Animals, Cells, Cultured, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic.

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.

DOI: 10.1194/jlr.M080242
PubMed: 29378782
PubMed Central: PMC5880492

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000629
to stream Main, to step Curation: 000629

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Autophagy (drug effects)</term>
<term>Cells, Cultured (MeSH)</term>
<term>Enzyme Inhibitors (chemistry)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Humans (MeSH)</term>
<term>Imipramine (chemistry)</term>
<term>Imipramine (pharmacology)</term>
<term>Lysosomes (drug effects)</term>
<term>Lysosomes (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Mice, Knockout (MeSH)</term>
<term>Mice, Transgenic (MeSH)</term>
<term>Multiprotein Complexes (antagonists & inhibitors)</term>
<term>Multiprotein Complexes (metabolism)</term>
<term>RNA, Small Interfering (chemistry)</term>
<term>RNA, Small Interfering (pharmacology)</term>
<term>Signal Transduction (drug effects)</term>
<term>Sphingomyelin Phosphodiesterase (antagonists & inhibitors)</term>
<term>Sphingomyelin Phosphodiesterase (deficiency)</term>
<term>Sphingomyelin Phosphodiesterase (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Antienzymes (composition chimique)</term>
<term>Antienzymes (pharmacologie)</term>
<term>Autophagie (effets des médicaments et des substances chimiques)</term>
<term>Cellules cultivées (MeSH)</term>
<term>Complexes multiprotéiques (antagonistes et inhibiteurs)</term>
<term>Complexes multiprotéiques (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Imipramine (composition chimique)</term>
<term>Imipramine (pharmacologie)</term>
<term>Lysosomes (effets des médicaments et des substances chimiques)</term>
<term>Lysosomes (métabolisme)</term>
<term>Petit ARN interférent (composition chimique)</term>
<term>Petit ARN interférent (pharmacologie)</term>
<term>Souris (MeSH)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Souris knockout (MeSH)</term>
<term>Souris transgéniques (MeSH)</term>
<term>Sphingomyeline phosphodiesterase (antagonistes et inhibiteurs)</term>
<term>Sphingomyeline phosphodiesterase (déficit)</term>
<term>Sphingomyeline phosphodiesterase (métabolisme)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Multiprotein Complexes</term>
<term>Sphingomyelin Phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Imipramine</term>
<term>RNA, Small Interfering</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Sphingomyelin Phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Sphingomyeline phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antienzymes</term>
<term>Imipramine</term>
<term>Petit ARN interférent</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term>
<term>Lysosomes</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Sphingomyeline phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Autophagie</term>
<term>Lysosomes</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lysosomes</term>
<term>Multiprotein Complexes</term>
<term>Sphingomyelin Phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Lysosomes</term>
<term>Sphingomyeline phosphodiesterase</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Imipramine</term>
<term>Petit ARN interférent</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Imipramine</term>
<term>RNA, Small Interfering</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cells, Cultured</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>Mice, Transgenic</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules cultivées</term>
<term>Humains</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Souris transgéniques</term>
</keywords>
</textClass>
</profileDesc>
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<front><div type="abstract" xml:lang="en">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 (<i>SMPD1</i>
) siRNA in human lung cells, or by transgenic <i>Smpd1</i>
<sup>+/-</sup>
 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.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29378782</PMID>
<DateCompleted><Year>2019</Year>
<Month>07</Month>
<Day>01</Day>
</DateCompleted>
<DateRevised><Year>2019</Year>
<Month>07</Month>
<Day>01</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1539-7262</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>59</Volume>
<Issue>4</Issue>
<PubDate><Year>2018</Year>
<Month>04</Month>
</PubDate>
</JournalIssue>
<Title>Journal of lipid research</Title>
<ISOAbbreviation>J Lipid Res</ISOAbbreviation>
</Journal>
<ArticleTitle>Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.</ArticleTitle>
<Pagination><MedlinePgn>596-606</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1194/jlr.M080242</ELocationID>
<Abstract><AbstractText>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 (<i>SMPD1</i>
) siRNA in human lung cells, or by transgenic <i>Smpd1</i>
<sup>+/-</sup>
 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.</AbstractText>
<CopyrightInformation>Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Justice</LastName>
<ForeName>Matthew J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medicine, National Jewish Health, Denver, CO 80206.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bronova</LastName>
<ForeName>Irina</ForeName>
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	Serveur d'exploration sur la rapamycine et les champignons
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Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

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