ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis

Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is ex...

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Veröffentlicht in:Cell metabolism 2024-03, Vol.36 (3), p.498-510.e11
Hauptverfasser: Chen, Chao, Zhang, Zhenxing, Liu, Caiyun, Sun, Pengkai, Liu, Ping, Li, Xinjian
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container_end_page 510.e11
container_issue 3
container_start_page 498
container_title Cell metabolism
container_volume 36
creator Chen, Chao
Zhang, Zhenxing
Liu, Caiyun
Sun, Pengkai
Liu, Ping
Li, Xinjian
description Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections. [Display omitted] •A custom-designed CRISPR screen identifies ABCG2 as an itaconate exporter•ABCG2 directly exports itaconate depending on its ATPase activity•ABCG2-mediated itaconate export alleviates TFEB-dependent lysosomal biogenesis•ABCG2-mediated itaconate export limits antibacterial innate immunity It has been reported that itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Here, Chen et al. reveal that ATP-binding cassette transporter G2 (ABCG2) is an itaconate exporter. ABCG2-mediated itaconate export limits antibacterial innate immunity by alleviating itaconate-induced TFEB activation and lysosomal biogenesis.
doi_str_mv 10.1016/j.cmet.2023.12.015
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However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections. [Display omitted] •A custom-designed CRISPR screen identifies ABCG2 as an itaconate exporter•ABCG2 directly exports itaconate depending on its ATPase activity•ABCG2-mediated itaconate export alleviates TFEB-dependent lysosomal biogenesis•ABCG2-mediated itaconate export limits antibacterial innate immunity It has been reported that itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Here, Chen et al. reveal that ATP-binding cassette transporter G2 (ABCG2) is an itaconate exporter. 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However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections. [Display omitted] •A custom-designed CRISPR screen identifies ABCG2 as an itaconate exporter•ABCG2 directly exports itaconate depending on its ATPase activity•ABCG2-mediated itaconate export alleviates TFEB-dependent lysosomal biogenesis•ABCG2-mediated itaconate export limits antibacterial innate immunity It has been reported that itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Here, Chen et al. reveal that ATP-binding cassette transporter G2 (ABCG2) is an itaconate exporter. ABCG2-mediated itaconate export limits antibacterial innate immunity by alleviating itaconate-induced TFEB activation and lysosomal biogenesis.</description><subject>ABCG2</subject><subject>Animals</subject><subject>Anti-Bacterial Agents</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>exporter</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>innate immunity</subject><subject>itaconate</subject><subject>lysosomal biogenesis</subject><subject>Lysosomes - metabolism</subject><subject>macrophages</subject><subject>Mice</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Succinates - metabolism</subject><subject>Succinates - pharmacology</subject><subject>TFEB</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u1DAURi1ERUvLC7BAXrJJ8E-c2BKbdlQKUiU23VuOfVPuKLGH2FMx4uXxdApLVrascz7Jh5D3nLWc8f7TtvULlFYwIVsuWsbVK3LBjRTN0An2ut6VYk3HJT8nb3PeMiZ7aeQbci4113zQ5oL8vr7Z3AmKmbpIsTifoitA4dcurQVWWn64QmdcsByJgqPz9RndTDE-k7gs-4jlQMcDdfMMT-gKxkf68OX2pgmwgxgg1olDTjkt1RsxPUKEjPmKnE1uzvDu5bwkVXrYfG3uv99921zfN16qvjRGecc4nzpupn7ixgMwGcygoJcyaGe0GIB3g-v6UIVhHCAE1Y1Baq1VJy_Jx9Psbk0_95CLXTB7mGcXIe2zFUZoY3otVUXFCfVrynmFye5WXNx6sJzZY3O7tcfm9tjccmFr8yp9eNnfjwuEf8rfyBX4fAKgfvIJYbXZI0QPAVfwxYaE_9v_A_m_lDY</recordid><startdate>20240305</startdate><enddate>20240305</enddate><creator>Chen, Chao</creator><creator>Zhang, Zhenxing</creator><creator>Liu, Caiyun</creator><creator>Sun, Pengkai</creator><creator>Liu, Ping</creator><creator>Li, Xinjian</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7480-7622</orcidid></search><sort><creationdate>20240305</creationdate><title>ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis</title><author>Chen, Chao ; Zhang, Zhenxing ; Liu, Caiyun ; Sun, Pengkai ; Liu, Ping ; Li, Xinjian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-95ca011f419f6f19cee03d975e633d8a9827e147a46d3567b7edd54bd3888543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>ABCG2</topic><topic>Animals</topic><topic>Anti-Bacterial Agents</topic><topic>ATP Binding Cassette Transporter, Subfamily G, Member 2</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>exporter</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>innate immunity</topic><topic>itaconate</topic><topic>lysosomal biogenesis</topic><topic>Lysosomes - metabolism</topic><topic>macrophages</topic><topic>Mice</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Succinates - metabolism</topic><topic>Succinates - pharmacology</topic><topic>TFEB</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chao</creatorcontrib><creatorcontrib>Zhang, Zhenxing</creatorcontrib><creatorcontrib>Liu, Caiyun</creatorcontrib><creatorcontrib>Sun, Pengkai</creatorcontrib><creatorcontrib>Liu, Ping</creatorcontrib><creatorcontrib>Li, Xinjian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chao</au><au>Zhang, Zhenxing</au><au>Liu, Caiyun</au><au>Sun, Pengkai</au><au>Liu, Ping</au><au>Li, Xinjian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2024-03-05</date><risdate>2024</risdate><volume>36</volume><issue>3</issue><spage>498</spage><epage>510.e11</epage><pages>498-510.e11</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><abstract>Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. 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subjects ABCG2
Animals
Anti-Bacterial Agents
ATP Binding Cassette Transporter, Subfamily G, Member 2
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
exporter
Humans
Immunity, Innate
innate immunity
itaconate
lysosomal biogenesis
Lysosomes - metabolism
macrophages
Mice
Neoplasm Proteins - metabolism
Succinates - metabolism
Succinates - pharmacology
TFEB
title ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis
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