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Beclin 2 negatively regulates innate immune signaling and tumor development
Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL...
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Published in: | The Journal of clinical investigation 2020-10, Vol.130 (10), p.5349-5369 |
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creator | Zhu, Motao Deng, Guangtong Tan, Peng Xing, Changsheng Guan, Cuiping Jiang, Chongming Zhang, Yinlong Ning, Bo Li, Chaoran Yin, Bingnan Chen, Kaifu Zhao, Yuliang Wang, Helen Y Levine, Beth Nie, Guangjun Wang, Rong-Fu |
description | Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer. |
doi_str_mv | 10.1172/JCI133283 |
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Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI133283</identifier><identifier>PMID: 32865519</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Ablation ; Animals ; Autophagy ; Autophagy - genetics ; Autophagy - immunology ; B cells ; Biomedical research ; Cancer ; Carcinogenesis - genetics ; Carcinogenesis - immunology ; Cytokines ; Cytokines - biosynthesis ; Development and progression ; Extracellular signal-regulated kinase ; HEK293 Cells ; Humans ; Immunity, Innate - genetics ; Inflammation ; Inflammation Mediators - metabolism ; Inflammatory diseases ; Intracellular Signaling Peptides and Proteins - deficiency ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - physiology ; Kinases ; Ligands ; Lymphadenopathy ; Lymphadenopathy - etiology ; Lymphadenopathy - genetics ; Lymphadenopathy - immunology ; Lymphatic system ; Lymphocytes ; Lymphoma ; MAP Kinase Signaling System - immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils ; NF-kappa B - metabolism ; NF-κB protein ; Non-Hodgkin's lymphomas ; Obesity ; Phenotypes ; Physiology ; Proteins ; Rodents ; Signal transduction ; Signal Transduction - genetics ; Signal Transduction - immunology ; Splenomegaly ; Splenomegaly - etiology ; Splenomegaly - genetics ; Splenomegaly - immunology ; Stat3 protein ; TAK1 protein ; Thymus gland ; Vesicles</subject><ispartof>The Journal of clinical investigation, 2020-10, Vol.130 (10), p.5349-5369</ispartof><rights>COPYRIGHT 2020 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Oct 2020</rights><rights>2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c607t-42bcb52c34f3ecc9e3675f159fdc9eb2afc744b84fc916b4bc5a973fed2395bc3</citedby><cites>FETCH-LOGICAL-c607t-42bcb52c34f3ecc9e3675f159fdc9eb2afc744b84fc916b4bc5a973fed2395bc3</cites><orcidid>0000-0001-9437-7244 ; 0000-0002-4424-9727 ; 0000-0003-1009-4357 ; 0000-0001-6582-9037</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524487/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524487/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32865519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Motao</creatorcontrib><creatorcontrib>Deng, Guangtong</creatorcontrib><creatorcontrib>Tan, Peng</creatorcontrib><creatorcontrib>Xing, Changsheng</creatorcontrib><creatorcontrib>Guan, Cuiping</creatorcontrib><creatorcontrib>Jiang, Chongming</creatorcontrib><creatorcontrib>Zhang, Yinlong</creatorcontrib><creatorcontrib>Ning, Bo</creatorcontrib><creatorcontrib>Li, Chaoran</creatorcontrib><creatorcontrib>Yin, Bingnan</creatorcontrib><creatorcontrib>Chen, Kaifu</creatorcontrib><creatorcontrib>Zhao, Yuliang</creatorcontrib><creatorcontrib>Wang, Helen Y</creatorcontrib><creatorcontrib>Levine, Beth</creatorcontrib><creatorcontrib>Nie, Guangjun</creatorcontrib><creatorcontrib>Wang, Rong-Fu</creatorcontrib><title>Beclin 2 negatively regulates innate immune signaling and tumor development</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.</description><subject>Ablation</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Autophagy - genetics</subject><subject>Autophagy - immunology</subject><subject>B cells</subject><subject>Biomedical research</subject><subject>Cancer</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - immunology</subject><subject>Cytokines</subject><subject>Cytokines - biosynthesis</subject><subject>Development and progression</subject><subject>Extracellular signal-regulated kinase</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunity, Innate - genetics</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>Inflammatory diseases</subject><subject>Intracellular Signaling Peptides and Proteins - deficiency</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - physiology</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Lymphadenopathy</subject><subject>Lymphadenopathy - etiology</subject><subject>Lymphadenopathy - genetics</subject><subject>Lymphadenopathy - immunology</subject><subject>Lymphatic system</subject><subject>Lymphocytes</subject><subject>Lymphoma</subject><subject>MAP Kinase Signaling System - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Neutrophils</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Non-Hodgkin's lymphomas</subject><subject>Obesity</subject><subject>Phenotypes</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - immunology</subject><subject>Splenomegaly</subject><subject>Splenomegaly - etiology</subject><subject>Splenomegaly - genetics</subject><subject>Splenomegaly - immunology</subject><subject>Stat3 protein</subject><subject>TAK1 protein</subject><subject>Thymus 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2 negatively regulates innate immune signaling and tumor development</title><author>Zhu, Motao ; Deng, Guangtong ; Tan, Peng ; Xing, Changsheng ; Guan, Cuiping ; Jiang, Chongming ; Zhang, Yinlong ; Ning, Bo ; Li, Chaoran ; Yin, Bingnan ; Chen, Kaifu ; Zhao, Yuliang ; Wang, Helen Y ; Levine, Beth ; Nie, Guangjun ; Wang, Rong-Fu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c607t-42bcb52c34f3ecc9e3675f159fdc9eb2afc744b84fc916b4bc5a973fed2395bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Ablation</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Autophagy - genetics</topic><topic>Autophagy - immunology</topic><topic>B cells</topic><topic>Biomedical research</topic><topic>Cancer</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - immunology</topic><topic>Cytokines</topic><topic>Cytokines - biosynthesis</topic><topic>Development and 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Motao</au><au>Deng, Guangtong</au><au>Tan, Peng</au><au>Xing, Changsheng</au><au>Guan, Cuiping</au><au>Jiang, Chongming</au><au>Zhang, Yinlong</au><au>Ning, Bo</au><au>Li, Chaoran</au><au>Yin, Bingnan</au><au>Chen, Kaifu</au><au>Zhao, Yuliang</au><au>Wang, Helen Y</au><au>Levine, Beth</au><au>Nie, Guangjun</au><au>Wang, Rong-Fu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Beclin 2 negatively regulates innate immune signaling and tumor development</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>130</volume><issue>10</issue><spage>5349</spage><epage>5369</epage><pages>5349-5369</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>32865519</pmid><doi>10.1172/JCI133283</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0001-9437-7244</orcidid><orcidid>https://orcid.org/0000-0002-4424-9727</orcidid><orcidid>https://orcid.org/0000-0003-1009-4357</orcidid><orcidid>https://orcid.org/0000-0001-6582-9037</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Ablation Animals Autophagy Autophagy - genetics Autophagy - immunology B cells Biomedical research Cancer Carcinogenesis - genetics Carcinogenesis - immunology Cytokines Cytokines - biosynthesis Development and progression Extracellular signal-regulated kinase HEK293 Cells Humans Immunity, Innate - genetics Inflammation Inflammation Mediators - metabolism Inflammatory diseases Intracellular Signaling Peptides and Proteins - deficiency Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - physiology Kinases Ligands Lymphadenopathy Lymphadenopathy - etiology Lymphadenopathy - genetics Lymphadenopathy - immunology Lymphatic system Lymphocytes Lymphoma MAP Kinase Signaling System - immunology Mice Mice, Inbred C57BL Mice, Knockout Neutrophils NF-kappa B - metabolism NF-κB protein Non-Hodgkin's lymphomas Obesity Phenotypes Physiology Proteins Rodents Signal transduction Signal Transduction - genetics Signal Transduction - immunology Splenomegaly Splenomegaly - etiology Splenomegaly - genetics Splenomegaly - immunology Stat3 protein TAK1 protein Thymus gland Vesicles |
title | Beclin 2 negatively regulates innate immune signaling and tumor development |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T22%3A46%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Beclin%202%20negatively%20regulates%20innate%20immune%20signaling%20and%20tumor%20development&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Zhu,%20Motao&rft.date=2020-10-01&rft.volume=130&rft.issue=10&rft.spage=5349&rft.epage=5369&rft.pages=5349-5369&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI133283&rft_dat=%3Cgale_pubme%3EA637941294%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c607t-42bcb52c34f3ecc9e3675f159fdc9eb2afc744b84fc916b4bc5a973fed2395bc3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2449506960&rft_id=info:pmid/32865519&rft_galeid=A637941294&rfr_iscdi=true |