Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.
Identifieur interne : 000894 ( Main/Exploration ); précédent : 000893; suivant : 000895Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.
Auteurs : Maroof Hasan [États-Unis] ; Vijay K. Gonugunta [États-Unis] ; Nicole Dobbs [États-Unis] ; Aktar Ali [États-Unis] ; Guillermo Palchik [États-Unis] ; Maria A. Calvaruso [États-Unis] ; Ralph J. Deberardinis [États-Unis] ; Nan Yan [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Complexe-1 cible mécanistique de la rapamycine (métabolisme), Facteur-3 de régulation d'interféron (métabolisme), Femelle (MeSH), Glycolyse (physiologie), Immunité innée (immunologie), Inflammation (immunologie), Inflammation (métabolisme), Matières grasses (métabolisme), Mitochondries (métabolisme), Mâle (MeSH), Métabolisme énergétique (physiologie), Nucléotides cycliques (métabolisme), Protein-Serine-Threonine Kinases (immunologie), Protein-Serine-Threonine Kinases (métabolisme), Protéines membranaires (métabolisme), Souris (MeSH), Souris de lignée C57BL (MeSH), Transduction du signal (immunologie), Transduction du signal (physiologie).
- MESH :
- immunologie : Immunité innée, Inflammation, Protein-Serine-Threonine Kinases, Transduction du signal.
- métabolisme : Complexe-1 cible mécanistique de la rapamycine, Facteur-3 de régulation d'interféron, Inflammation, Matières grasses, Mitochondries, Nucléotides cycliques, Protein-Serine-Threonine Kinases, Protéines membranaires.
- physiologie : Glycolyse, Métabolisme énergétique, Transduction du signal.
- Animaux, Femelle, Mâle, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals (MeSH), Energy Metabolism (physiology), Fats (metabolism), Female (MeSH), Glycolysis (physiology), Immunity, Innate (immunology), Inflammation (immunology), Inflammation (metabolism), Interferon Regulatory Factor-3 (metabolism), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (metabolism), Membrane Proteins (metabolism), Mice (MeSH), Mice, Inbred C57BL (MeSH), Mitochondria (metabolism), Nucleotides, Cyclic (metabolism), Protein-Serine-Threonine Kinases (immunology), Protein-Serine-Threonine Kinases (metabolism), Signal Transduction (immunology), Signal Transduction (physiology).
- MESH :
- chemical , immunology : Protein-Serine-Threonine Kinases.
- chemical , metabolism : Fats, Interferon Regulatory Factor-3, Mechanistic Target of Rapamycin Complex 1, Membrane Proteins, Nucleotides, Cyclic, Protein-Serine-Threonine Kinases.
- immunology : Immunity, Innate, Inflammation, Signal Transduction.
- metabolism : Inflammation, Mitochondria.
- physiology : Energy Metabolism, Glycolysis, Signal Transduction.
- Animals, Female, Male, Mice, Mice, Inbred C57BL.
Abstract
Three-prime repair exonuclease 1 knockout (Trex1-/-) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1-/- mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1-/- background, and many metabolic defects persist in Trex1-/-Irf3-/- cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1-/- mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1-/- cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.
DOI: 10.1073/pnas.1611113114
PubMed: 28069950
PubMed Central: PMC5278463
Affiliations:
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Gonugunta</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Immunology, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Dobbs, Nicole" sort="Dobbs, Nicole" uniqKey="Dobbs N" first="Nicole" last="Dobbs">Nicole Dobbs</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Immunology, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Ali, Aktar" sort="Ali, Aktar" uniqKey="Ali A" first="Aktar" last="Ali">Aktar Ali</name><affiliation wicri:level="2"><nlm:affiliation>Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Palchik, Guillermo" sort="Palchik, Guillermo" uniqKey="Palchik G" first="Guillermo" last="Palchik">Guillermo Palchik</name><affiliation wicri:level="2"><nlm:affiliation>Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Calvaruso, Maria A" sort="Calvaruso, Maria A" uniqKey="Calvaruso M" first="Maria A" last="Calvaruso">Maria A. Calvaruso</name><affiliation wicri:level="2"><nlm:affiliation>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Deberardinis, Ralph J" sort="Deberardinis, Ralph J" uniqKey="Deberardinis R" first="Ralph J" last="Deberardinis">Ralph J. Deberardinis</name><affiliation wicri:level="2"><nlm:affiliation>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author><author><name sortKey="Yan, Nan" sort="Yan, Nan" uniqKey="Yan N" first="Nan" last="Yan">Nan Yan</name><affiliation wicri:level="3"><nlm:affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; nan.yan@utsouthwestern.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Immunology, University of Texas Southwestern Medical Center, Dallas</wicri:regionArea><placeName><settlement type="city">Dallas</settlement><region type="state">Texas</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Microbiology, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Energy Metabolism (physiology)</term><term>Fats (metabolism)</term><term>Female (MeSH)</term><term>Glycolysis (physiology)</term><term>Immunity, Innate (immunology)</term><term>Inflammation (immunology)</term><term>Inflammation (metabolism)</term><term>Interferon Regulatory Factor-3 (metabolism)</term><term>Male (MeSH)</term><term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term><term>Membrane Proteins (metabolism)</term><term>Mice (MeSH)</term><term>Mice, Inbred C57BL (MeSH)</term><term>Mitochondria (metabolism)</term><term>Nucleotides, Cyclic (metabolism)</term><term>Protein-Serine-Threonine Kinases (immunology)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>Signal Transduction (immunology)</term><term>Signal Transduction (physiology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term><term>Facteur-3 de régulation d'interféron (métabolisme)</term><term>Femelle (MeSH)</term><term>Glycolyse (physiologie)</term><term>Immunité innée (immunologie)</term><term>Inflammation (immunologie)</term><term>Inflammation (métabolisme)</term><term>Matières grasses (métabolisme)</term><term>Mitochondries (métabolisme)</term><term>Mâle (MeSH)</term><term>Métabolisme énergétique (physiologie)</term><term>Nucléotides cycliques (métabolisme)</term><term>Protein-Serine-Threonine Kinases (immunologie)</term><term>Protein-Serine-Threonine Kinases (métabolisme)</term><term>Protéines membranaires (métabolisme)</term><term>Souris (MeSH)</term><term>Souris de lignée C57BL (MeSH)</term><term>Transduction du signal (immunologie)</term><term>Transduction du signal (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Fats</term><term>Interferon Regulatory Factor-3</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Membrane Proteins</term><term>Nucleotides, Cyclic</term><term>Protein-Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Immunité innée</term><term>Inflammation</term><term>Protein-Serine-Threonine Kinases</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Immunity, Innate</term><term>Inflammation</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Inflammation</term><term>Mitochondria</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Facteur-3 de régulation d'interféron</term><term>Inflammation</term><term>Matières grasses</term><term>Mitochondries</term><term>Nucléotides cycliques</term><term>Protein-Serine-Threonine Kinases</term><term>Protéines membranaires</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Glycolyse</term><term>Métabolisme énergétique</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Energy Metabolism</term><term>Glycolysis</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Female</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Mâle</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Three-prime repair exonuclease 1 knockout (Trex1<sup>-/-</sup>) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1<sup>-/-</sup> mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1<sup>-/-</sup> background, and many metabolic defects persist in Trex1<sup>-/-</sup>Irf3<sup>-/-</sup> cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1<sup>-/-</sup> mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1<sup>-/-</sup> cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28069950</PMID><DateCompleted><Year>2018</Year><Month>04</Month><Day>09</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN><JournalIssue CitedMedium="Internet"><Volume>114</Volume><Issue>4</Issue><PubDate><Year>2017</Year><Month>01</Month><Day>24</Day></PubDate></JournalIssue><Title>Proceedings of the National Academy of Sciences of the United States of America</Title><ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation></Journal><ArticleTitle>Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.</ArticleTitle><Pagination><MedlinePgn>746-751</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1611113114</ELocationID><Abstract><AbstractText>Three-prime repair exonuclease 1 knockout (Trex1<sup>-/-</sup>) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1<sup>-/-</sup> mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1<sup>-/-</sup> background, and many metabolic defects persist in Trex1<sup>-/-</sup>Irf3<sup>-/-</sup> cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1<sup>-/-</sup> mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1<sup>-/-</sup> cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hasan</LastName><ForeName>Maroof</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gonugunta</LastName><ForeName>Vijay K</ForeName><Initials>VK</Initials><AffiliationInfo><Affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dobbs</LastName><ForeName>Nicole</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ali</LastName><ForeName>Aktar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Palchik</LastName><ForeName>Guillermo</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Calvaruso</LastName><ForeName>Maria A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>DeBerardinis</LastName><ForeName>Ralph J</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yan</LastName><ForeName>Nan</ForeName><Initials>N</Initials><Identifier Source="ORCID">0000-0002-0637-3989</Identifier><AffiliationInfo><Affiliation>Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; nan.yan@utsouthwestern.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 AI098569</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AR067135</GrantID><Acronym>AR</Acronym><Agency>NIAMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>01</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Proc Natl Acad Sci U S A</MedlineTA><NlmUniqueID>7505876</NlmUniqueID><ISSNLinking>0027-8424</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005223">Fats</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D050838">Interferon Regulatory Factor-3</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008565">Membrane Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009712">Nucleotides, Cyclic</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C584311">cyclic guanosine monophosphate-adenosine monophosphate</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber><NameOfSubstance UI="C498588">Tbk1 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D017346">Protein-Serine-Threonine Kinases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004734" MajorTopicYN="N">Energy Metabolism</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005223" MajorTopicYN="N">Fats</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006019" MajorTopicYN="N">Glycolysis</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007113" MajorTopicYN="N">Immunity, Innate</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007249" MajorTopicYN="N">Inflammation</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050838" MajorTopicYN="N">Interferon Regulatory Factor-3</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008565" MajorTopicYN="N">Membrane Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008928" MajorTopicYN="N">Mitochondria</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009712" MajorTopicYN="N">Nucleotides, Cyclic</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017346" MajorTopicYN="N">Protein-Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">TBK1</Keyword><Keyword MajorTopicYN="Y">TREX1</Keyword><Keyword MajorTopicYN="Y">innate immunity</Keyword><Keyword MajorTopicYN="Y">mTORC1</Keyword><Keyword MajorTopicYN="Y">metabolism</Keyword></KeywordList><CoiStatement>The authors declare no conflict of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>1</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>4</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>1</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28069950</ArticleId><ArticleId 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