C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.
Identifieur interne : 000161 ( Main/Exploration ); précédent : 000160; suivant : 000162C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.
Auteurs : Qiang Shao [États-Unis] ; Mei Yang [États-Unis, République populaire de Chine] ; Chen Liang [États-Unis] ; Li Ma [États-Unis] ; Wei Zhang [États-Unis] ; Zhiwen Jiang [République populaire de Chine] ; Jun Luo [République populaire de Chine] ; Jae-Kyung Lee [États-Unis] ; Chengyu Liang [États-Unis] ; Jian-Fu Chen [États-Unis]Source :
- Autophagy [ 1554-8635 ] ; 2020.
Abstract
How lysosome and MTORC1 signaling interact remains elusive in terminally differentiated cells. A G4C2 repeat expansion in C9orf72 is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS-FTD). We previously identified a C9orf72-SMCR8-containing complex. Here we found that c9orf72 and smcr8 double-knockout (dKO) mice exhibit similar but more severe immune defects than the individual knockouts. In c9orf72 or smcr8 mutant macrophages, lysosomal degradation and exocytosis were impaired due to the disruption of autolysosome acidification. As a result of impaired lysosomal degradation, MTOR protein was aberrantly increased, resulting in MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction, splenomegaly and lymphadenopathy in c9orf72 or smcr8 mutant mice. Pharmacological inhibition of lysosomal degradation upregulated MTOR protein and MTORC1 signaling in differentiated wild-type macrophages, which resemble phenotypes in KO mice. In contrast, C9orf72 or Smcr8 depletion in proliferating macrophages decreased MTORC1 signaling. Our studies causatively link C9orf72-SMCR8's cellular functions in lysosomal degradation, exocytosis, and MTORC1 signaling with their organism-level immune regulation, suggesting cell state (proliferation vs. differentiation)-dependent regulation of MTOR signaling via lysosomes.Abbreviations: ALS: amyotrophic lateral sclerosis; ATG13: autophagy related 13; BMDMs: bone marrow-derived macrophages; BafA1: bafilomycin A1; C9orf72: C9orf72, member of C9orf72-SMCR8 complex; CD68: CD68 antigen; ConA: concanamycin A; dKO: double knockout; DENN: differentially expressed in normal and neoplastic cells; FTD: frontotemporal dementia; GEF: guanine nucleotide exchange factor; IFNB1: interferon beta 1, fibroblast; IFNG: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; iPSCs: induced pluripotent stem cells; LAMP1: lysosomal-associated membrane protein 1; LPOs: LAMP1-positive organelles; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LPS: lipopolysaccharide; MTORC1: mechanistic target of rapamycin kinase complex 1; MEFs: mouse embryonic fibroblasts; MNs: motor neurons; NOS2/iNOS: nitric oxide synthase 2, inducible; RAN: repeat-associated non-AUG; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RPS6/S6: ribosomal protein S6; RPS6KB1/S6K1: ribosomal protein S6 kinase, polypeptide 1; SMCR8: Smith-Magenis syndrome chromosome region, candidate 8; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNF: tumor necrosis factor; TSC1: TSC complex subunit 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H⁺-translocating ATPase.
DOI: 10.1080/15548627.2019.1703353
PubMed: 31847700
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China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Center for Life Sciences, School of Life Sciences, Yunnan University , Kunming</wicri:regionArea><wicri:noRegion>Kunming</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Chen" sort="Liang, Chen" uniqKey="Liang C" first="Chen" last="Liang">Chen Liang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Cellular Biology, University of Georgia , Athens, GA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cellular Biology, University of Georgia , Athens, GA</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Ma, Li" sort="Ma, Li" uniqKey="Ma L" first="Li" last="Ma">Li Ma</name><affiliation wicri:level="2"><nlm:affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name><affiliation wicri:level="2"><nlm:affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Jiang, Zhiwen" sort="Jiang, Zhiwen" uniqKey="Jiang Z" first="Zhiwen" last="Jiang">Zhiwen Jiang</name><affiliation wicri:level="1"><nlm:affiliation>Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University , Dongguan, Guangdong, P.R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University , Dongguan, Guangdong</wicri:regionArea><wicri:noRegion>Guangdong</wicri:noRegion></affiliation></author><author><name sortKey="Luo, Jun" sort="Luo, Jun" uniqKey="Luo J" first="Jun" last="Luo">Jun Luo</name><affiliation wicri:level="1"><nlm:affiliation>Division of VIP Center, Stomatological Hospital of Chongqing Medical University , Chongqing, P.R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Division of VIP Center, Stomatological Hospital of Chongqing Medical University , Chongqing</wicri:regionArea><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Jae Kyung" sort="Lee, Jae Kyung" uniqKey="Lee J" first="Jae-Kyung" last="Lee">Jae-Kyung Lee</name><affiliation wicri:level="2"><nlm:affiliation>Department of Physiology and Pharmacology, University of Georgia , Athens, GA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology and Pharmacology, University of Georgia , Athens, GA</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Liang, Chengyu" sort="Liang, Chengyu" uniqKey="Liang C" first="Chengyu" last="Liang">Chengyu Liang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California , Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California , Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Chen, Jian Fu" sort="Chen, Jian Fu" uniqKey="Chen J" first="Jian-Fu" last="Chen">Jian-Fu Chen</name><affiliation wicri:level="2"><nlm:affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">How lysosome and MTORC1 signaling interact remains elusive in terminally differentiated cells. A G4C2 repeat expansion in <i>C9orf72</i> is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS-FTD). We previously identified a C9orf72-SMCR8-containing complex. Here we found that <i>c9orf72</i> and <i>smcr8</i> double-knockout (dKO) mice exhibit similar but more severe immune defects than the individual <i>knockouts</i>. In <i>c9orf72</i> or <i>smcr8</i> mutant macrophages, lysosomal degradation and exocytosis were impaired due to the disruption of autolysosome acidification. As a result of impaired lysosomal degradation, MTOR protein was aberrantly increased, resulting in MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction, splenomegaly and lymphadenopathy in <i>c9orf72</i> or <i>smcr8</i> mutant mice. Pharmacological inhibition of lysosomal degradation upregulated MTOR protein and MTORC1 signaling in differentiated wild-type macrophages, which resemble phenotypes in KO mice. In contrast, <i>C9orf72</i> or <i>Smcr8</i> depletion in proliferating macrophages decreased MTORC1 signaling. Our studies causatively link C9orf72-SMCR8's cellular functions in lysosomal degradation, exocytosis, and MTORC1 signaling with their organism-level immune regulation, suggesting cell state (proliferation vs. differentiation)-dependent regulation of MTOR signaling via lysosomes.<b>Abbreviations</b>: ALS: amyotrophic lateral sclerosis; ATG13: autophagy related 13; BMDMs: bone marrow-derived macrophages; BafA<sub>1</sub>: bafilomycin A<sub>1</sub>; C9orf72: C9orf72, member of C9orf72-SMCR8 complex; CD68: CD68 antigen; ConA: concanamycin A; dKO: double knockout; DENN: differentially expressed in normal and neoplastic cells; FTD: frontotemporal dementia; GEF: guanine nucleotide exchange factor; IFNB1: interferon beta 1, fibroblast; IFNG: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; iPSCs: induced pluripotent stem cells; LAMP1: lysosomal-associated membrane protein 1; LPOs: LAMP1-positive organelles; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LPS: lipopolysaccharide; MTORC1: mechanistic target of rapamycin kinase complex 1; MEFs: mouse embryonic fibroblasts; MNs: motor neurons; NOS2/iNOS: nitric oxide synthase 2, inducible; RAN: repeat-associated non-AUG; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RPS6/S6: ribosomal protein S6; RPS6KB1/S6K1: ribosomal protein S6 kinase, polypeptide 1; SMCR8: Smith-Magenis syndrome chromosome region, candidate 8; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNF: tumor necrosis factor; TSC1: TSC complex subunit 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H⁺-translocating ATPase.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">31847700</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>02</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><Volume>16</Volume><Issue>9</Issue><PubDate><Year>2020</Year><Month>09</Month></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle><i>C9orf72</i> and <i>smcr8</i> mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.</ArticleTitle><Pagination><MedlinePgn>1635-1650</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/15548627.2019.1703353</ELocationID><Abstract><AbstractText>How lysosome and MTORC1 signaling interact remains elusive in terminally differentiated cells. A G4C2 repeat expansion in <i>C9orf72</i> is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS-FTD). We previously identified a C9orf72-SMCR8-containing complex. Here we found that <i>c9orf72</i> and <i>smcr8</i> double-knockout (dKO) mice exhibit similar but more severe immune defects than the individual <i>knockouts</i>. In <i>c9orf72</i> or <i>smcr8</i> mutant macrophages, lysosomal degradation and exocytosis were impaired due to the disruption of autolysosome acidification. As a result of impaired lysosomal degradation, MTOR protein was aberrantly increased, resulting in MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction, splenomegaly and lymphadenopathy in <i>c9orf72</i> or <i>smcr8</i> mutant mice. Pharmacological inhibition of lysosomal degradation upregulated MTOR protein and MTORC1 signaling in differentiated wild-type macrophages, which resemble phenotypes in KO mice. In contrast, <i>C9orf72</i> or <i>Smcr8</i> depletion in proliferating macrophages decreased MTORC1 signaling. Our studies causatively link C9orf72-SMCR8's cellular functions in lysosomal degradation, exocytosis, and MTORC1 signaling with their organism-level immune regulation, suggesting cell state (proliferation vs. differentiation)-dependent regulation of MTOR signaling via lysosomes.<b>Abbreviations</b>: ALS: amyotrophic lateral sclerosis; ATG13: autophagy related 13; BMDMs: bone marrow-derived macrophages; BafA<sub>1</sub>: bafilomycin A<sub>1</sub>; C9orf72: C9orf72, member of C9orf72-SMCR8 complex; CD68: CD68 antigen; ConA: concanamycin A; dKO: double knockout; DENN: differentially expressed in normal and neoplastic cells; FTD: frontotemporal dementia; GEF: guanine nucleotide exchange factor; IFNB1: interferon beta 1, fibroblast; IFNG: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; iPSCs: induced pluripotent stem cells; LAMP1: lysosomal-associated membrane protein 1; LPOs: LAMP1-positive organelles; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LPS: lipopolysaccharide; MTORC1: mechanistic target of rapamycin kinase complex 1; MEFs: mouse embryonic fibroblasts; MNs: motor neurons; NOS2/iNOS: nitric oxide synthase 2, inducible; RAN: repeat-associated non-AUG; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RPS6/S6: ribosomal protein S6; RPS6KB1/S6K1: ribosomal protein S6 kinase, polypeptide 1; SMCR8: Smith-Magenis syndrome chromosome region, candidate 8; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNF: tumor necrosis factor; TSC1: TSC complex subunit 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H⁺-translocating ATPase.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Shao</LastName><ForeName>Qiang</ForeName><Initials>Q</Initials><Identifier Source="ORCID">0000-0001-5307-8264</Identifier><AffiliationInfo><Affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Mei</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center for Life Sciences, School of Life Sciences, Yunnan University , Kunming, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liang</LastName><ForeName>Chen</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Cellular Biology, University of Georgia , Athens, GA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ma</LastName><ForeName>Li</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jiang</LastName><ForeName>Zhiwen</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University , Dongguan, Guangdong, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Luo</LastName><ForeName>Jun</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Division of VIP Center, Stomatological Hospital of Chongqing Medical University , Chongqing, P.R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Jae-Kyung</ForeName><Initials>JK</Initials><AffiliationInfo><Affiliation>Department of Physiology and Pharmacology, University of Georgia , Athens, GA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liang</LastName><ForeName>Chengyu</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Jian-Fu</ForeName><Initials>JF</Initials><AffiliationInfo><Affiliation>Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 NS096176</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 NS097231</GrantID><Acronym>NS</Acronym><Agency>NINDS 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></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>12</Month><Day>26</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Autophagy</MedlineTA><NlmUniqueID>101265188</NlmUniqueID><ISSNLinking>1554-8627</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">C9orf72</Keyword><Keyword MajorTopicYN="Y">MTORC1</Keyword><Keyword MajorTopicYN="Y">SMCR8</Keyword><Keyword MajorTopicYN="Y">lysosomal degradation</Keyword><Keyword MajorTopicYN="Y">lysosomal exocytosis</Keyword><Keyword MajorTopicYN="Y">macrophage</Keyword><Keyword MajorTopicYN="Y">mice</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31847700</ArticleId><ArticleId IdType="doi">10.1080/15548627.2019.1703353</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Californie</li><li>Géorgie (États-Unis)</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Shao, Qiang" sort="Shao, Qiang" uniqKey="Shao Q" first="Qiang" last="Shao">Qiang Shao</name></region><name sortKey="Chen, Jian Fu" sort="Chen, Jian Fu" uniqKey="Chen J" first="Jian-Fu" last="Chen">Jian-Fu Chen</name><name sortKey="Lee, Jae Kyung" sort="Lee, Jae Kyung" uniqKey="Lee J" first="Jae-Kyung" last="Lee">Jae-Kyung Lee</name><name sortKey="Liang, Chen" sort="Liang, Chen" uniqKey="Liang C" first="Chen" last="Liang">Chen Liang</name><name sortKey="Liang, Chengyu" sort="Liang, Chengyu" uniqKey="Liang C" first="Chengyu" last="Liang">Chengyu Liang</name><name sortKey="Ma, Li" sort="Ma, Li" uniqKey="Ma L" first="Li" last="Ma">Li Ma</name><name sortKey="Yang, Mei" sort="Yang, Mei" uniqKey="Yang M" first="Mei" last="Yang">Mei Yang</name><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Yang, Mei" sort="Yang, Mei" uniqKey="Yang M" first="Mei" last="Yang">Mei Yang</name></noRegion><name sortKey="Jiang, Zhiwen" sort="Jiang, Zhiwen" uniqKey="Jiang Z" first="Zhiwen" last="Jiang">Zhiwen Jiang</name><name sortKey="Luo, Jun" sort="Luo, Jun" uniqKey="Luo J" first="Jun" last="Luo">Jun Luo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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