RapamycinFungusV1, Main, Exploration, bibRecord, 000418

mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.

Identifieur interne : 000418 ( Main/Exploration ); précédent : 000417; suivant : 000419

mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.

Auteurs : Andrew J. Monteith [États-Unis] ; Heather A. Vincent [États-Unis] ; Sunah Kang [États-Unis] ; Patrick Li [États-Unis] ; Tauris M. Claiborne [États-Unis] ; Zenon Rajfur [États-Unis, Pologne] ; Ken Jacobson [États-Unis] ; Nathaniel J. Moorman [États-Unis] ; Barbara J. Vilen [États-Unis]

Source :

Journal of immunology (Baltimore, Md. : 1950) [ 1550-6606 ] ; 2018.

RBID : pubmed:29866702

Descripteurs français

English descriptors

KwdEn :
- Animals (MeSH), Antigen-Antibody Complex (metabolism), Apoptosis (physiology), Caspase 1 (metabolism), Homeostasis (physiology), Inflammasomes (metabolism), Lupus Erythematosus, Systemic (metabolism), Lysosomes (metabolism), Macrophages (metabolism), Mechanistic Target of Rapamycin Complex 2 (metabolism), Mice (MeSH), Mice, Inbred C57BL (MeSH), Phagocytosis (physiology), Phagosomes (metabolism), Pyroptosis (physiology), Signal Transduction (physiology), rab GTP-Binding Proteins (metabolism).
MESH :
- chemical , metabolism : Antigen-Antibody Complex, Caspase 1, Inflammasomes, Mechanistic Target of Rapamycin Complex 2, rab GTP-Binding Proteins.
- metabolism : Lupus Erythematosus, Systemic, Lysosomes, Macrophages, Phagosomes.
- physiology : Apoptosis, Homeostasis, Phagocytosis, Pyroptosis, Signal Transduction.
- Animals, Mice, Mice, Inbred C57BL.

Abstract

Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcγRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus.

DOI: 10.4049/jimmunol.1701712
PubMed: 29866702
PubMed Central: PMC6039264

Affiliations:

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

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Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.</title>
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<series><title level="j">Journal of immunology (Baltimore, Md. : 1950)</title>
<idno type="eISSN">1550-6606</idno>
<imprint><date when="2018" type="published">2018</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Antigen-Antibody Complex (metabolism)</term>
<term>Apoptosis (physiology)</term>
<term>Caspase 1 (metabolism)</term>
<term>Homeostasis (physiology)</term>
<term>Inflammasomes (metabolism)</term>
<term>Lupus Erythematosus, Systemic (metabolism)</term>
<term>Lysosomes (metabolism)</term>
<term>Macrophages (metabolism)</term>
<term>Mechanistic Target of Rapamycin Complex 2 (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Phagocytosis (physiology)</term>
<term>Phagosomes (metabolism)</term>
<term>Pyroptosis (physiology)</term>
<term>Signal Transduction (physiology)</term>
<term>rab GTP-Binding Proteins (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Apoptose (physiologie)</term>
<term>Caspase-1 (métabolisme)</term>
<term>Complexe antigène-anticorps (métabolisme)</term>
<term>Complexe-2 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Homéostasie (physiologie)</term>
<term>Inflammasomes (métabolisme)</term>
<term>Lupus érythémateux disséminé (métabolisme)</term>
<term>Lysosomes (métabolisme)</term>
<term>Macrophages (métabolisme)</term>
<term>Phagocytose (physiologie)</term>
<term>Phagosomes (métabolisme)</term>
<term>Protéines G rab (métabolisme)</term>
<term>Pyroptose (physiologie)</term>
<term>Souris (MeSH)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Transduction du signal (physiologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigen-Antibody Complex</term>
<term>Caspase 1</term>
<term>Inflammasomes</term>
<term>Mechanistic Target of Rapamycin Complex 2</term>
<term>rab GTP-Binding Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lupus Erythematosus, Systemic</term>
<term>Lysosomes</term>
<term>Macrophages</term>
<term>Phagosomes</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Caspase-1</term>
<term>Complexe antigène-anticorps</term>
<term>Complexe-2 cible mécanistique de la rapamycine</term>
<term>Inflammasomes</term>
<term>Lupus érythémateux disséminé</term>
<term>Lysosomes</term>
<term>Macrophages</term>
<term>Phagosomes</term>
<term>Protéines G rab</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Apoptose</term>
<term>Homéostasie</term>
<term>Phagocytose</term>
<term>Pyroptose</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Apoptosis</term>
<term>Homeostasis</term>
<term>Phagocytosis</term>
<term>Pyroptosis</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcγRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus.</div>
</front>
</TEI>
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<DateCompleted><Year>2019</Year>
<Month>06</Month>
<Day>21</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>06</Day>
</DateRevised>
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<JournalIssue CitedMedium="Internet"><Volume>201</Volume>
<Issue>2</Issue>
<PubDate><Year>2018</Year>
<Month>07</Month>
<Day>15</Day>
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<Title>Journal of immunology (Baltimore, Md. : 1950)</Title>
<ISOAbbreviation>J Immunol</ISOAbbreviation>
</Journal>
<ArticleTitle>mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.</ArticleTitle>
<Pagination><MedlinePgn>371-382</MedlinePgn>
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<Abstract><AbstractText>Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcγRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus.</AbstractText>
<CopyrightInformation>Copyright © 2018 by The American Association of Immunologists, Inc.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Monteith</LastName>
<ForeName>Andrew J</ForeName>
<Initials>AJ</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.</Affiliation>
</AffiliationInfo>
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<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Kang</LastName>
<ForeName>SunAh</ForeName>
<Initials>S</Initials>
<Identifier Source="ORCID">0000-0002-6327-184X</Identifier>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Patrick</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.</Affiliation>
</AffiliationInfo>
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<ForeName>Tauris M</ForeName>
<Initials>TM</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rajfur</LastName>
<ForeName>Zenon</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Physics, Astronomy, and Applied Computer Science, Institute of Physics, Jagiellonian University, 31-007 Krakow, Poland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jacobson</LastName>
<ForeName>Ken</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.</Affiliation>
</AffiliationInfo>
</Author>
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	Serveur d'exploration sur la rapamycine et les champignons
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mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.

mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a.

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