Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1
Significance In this study, we demonstrate that guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) regulate the downstream signaling pathways of Toll-like receptor 4 (TLR4). We show that Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and grow...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2015-04, Vol.112 (15), p.4731-4736 |
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| creator | Li, Xianjing Wang, Duowei Chen, Zhen Lu, Ermei Wang, Zhuo Duan, Jingjing Tian, Wei Wang, Yun You, Linjun Zou, Yulian Cheng, Yan Zhu, Qingyi Wan, Xiaojian Xi, Tao Jiang, Meisheng Han, Yuyuan Cao, Cong Birnbaumer, Lutz Chu, Wen-Ming Yang, Yong |
| description | Significance In this study, we demonstrate that guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) regulate the downstream signaling pathways of Toll-like receptor 4 (TLR4). We show that Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling and NF-κB activation. Besides, Gα ᵢ₁/₃ act at both the plasma membrane and the endosome levels and are involved in TLR4 endocytosis. Furthermore, Gα ᵢ₁/₃ participated in the induction of M1 polarization of macrophages, and their decreased expression contributed to LPS tolerance. Thus, Gα ᵢ₁/₃ are important in controlling inflammation.
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gα ᵢ₁/₃ deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gα ᵢ₁/₃ knockdown in bone marrow-derived macrophage cells (Gα ᵢ₁/₃ KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gα ᵢ₁/₃ deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gα ᵢ₁/₃ were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gα ᵢ₁/₃ can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo. |
| doi_str_mv | 10.1073/pnas.1503779112 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pnas_</sourceid><recordid>TN_cdi_pnas_primary_112_15_4731</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1803078443</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3892-905131e3932576e987401c9ef66463e45f0201790787bf3cc7a737ece989dac83</originalsourceid><addsrcrecordid>eNpVkcFu1DAQhi0EokvhzA1y5JJ2JnZi-4KEFlqQKnFoe7ZmvU4alMTBziLKDfomvAEHXoN3gCfB0W6XcrJsf_PNaH7GniIcIUh-PA4Uj7AELqVGLO6xBYLGvBIa7rMFQCFzJQpxwB7F-AEAdKngITsoSlWUUuCC1ae_fvz--f3Pt68ZDevs9naTBddsOppc1pMNfryixmWj7yi0X2hq_ZCtrrPah74dmowy6_uxc5_TOUzUDvPj8jWKrZNW-Jg9qKmL7snuPGSXJ28ulm_zs_en75avznLLlS5yDSVydFzzNF7ltJIC0GpXV5WouBNlDQWg1CCVXNXcWkmSS2cTqddkFT9kL7fecbPq3dq6YQrUmTG0PYVr46k1__8M7ZVp_CcjBHBUs-DFThD8x42Lk-nbaF3X0eD8JhpUwFN3IXhCj7do2k-MwdX7NghmTsfM6Zh_6aSKZ3en2_O3cSTg-Q6YK_c6LJLFCMnvEDV5Q01oo7k8TzupAJDrQij-F-GEo2M</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1803078443</pqid></control><display><type>article</type><title>Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1</title><source>Jstor Complete Legacy</source><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Li, Xianjing ; Wang, Duowei ; Chen, Zhen ; Lu, Ermei ; Wang, Zhuo ; Duan, Jingjing ; Tian, Wei ; Wang, Yun ; You, Linjun ; Zou, Yulian ; Cheng, Yan ; Zhu, Qingyi ; Wan, Xiaojian ; Xi, Tao ; Jiang, Meisheng ; Han, Yuyuan ; Cao, Cong ; Birnbaumer, Lutz ; Chu, Wen-Ming ; Yang, Yong</creator><creatorcontrib>Li, Xianjing ; Wang, Duowei ; Chen, Zhen ; Lu, Ermei ; Wang, Zhuo ; Duan, Jingjing ; Tian, Wei ; Wang, Yun ; You, Linjun ; Zou, Yulian ; Cheng, Yan ; Zhu, Qingyi ; Wan, Xiaojian ; Xi, Tao ; Jiang, Meisheng ; Han, Yuyuan ; Cao, Cong ; Birnbaumer, Lutz ; Chu, Wen-Ming ; Yang, Yong</creatorcontrib><description>Significance In this study, we demonstrate that guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) regulate the downstream signaling pathways of Toll-like receptor 4 (TLR4). We show that Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling and NF-κB activation. Besides, Gα ᵢ₁/₃ act at both the plasma membrane and the endosome levels and are involved in TLR4 endocytosis. Furthermore, Gα ᵢ₁/₃ participated in the induction of M1 polarization of macrophages, and their decreased expression contributed to LPS tolerance. Thus, Gα ᵢ₁/₃ are important in controlling inflammation.
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gα ᵢ₁/₃ deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gα ᵢ₁/₃ knockdown in bone marrow-derived macrophage cells (Gα ᵢ₁/₃ KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gα ᵢ₁/₃ deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gα ᵢ₁/₃ were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gα ᵢ₁/₃ can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1503779112</identifier><identifier>PMID: 25825741</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptor Proteins, Signal Transducing ; Animals ; Biological Sciences ; Blotting, Western ; Cell Line, Tumor ; Cells, Cultured ; endocytosis ; Endocytosis - drug effects ; G-proteins ; GTP-Binding Protein alpha Subunits, Gi-Go - genetics ; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism ; Humans ; inflammation ; Interleukin-12 - metabolism ; Interleukin-6 - metabolism ; Lipopolysaccharide Receptors - genetics ; Lipopolysaccharide Receptors - metabolism ; Lipopolysaccharides - pharmacology ; macrophages ; Macrophages - drug effects ; Macrophages - metabolism ; Macrophages, Peritoneal - drug effects ; Macrophages, Peritoneal - metabolism ; Mice, 129 Strain ; Mice, Knockout ; Microscopy, Confocal ; Mitogen-Activated Protein Kinases - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; plasma membrane ; Protein Binding - drug effects ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; signal transduction ; Survival Analysis ; Toll-like receptor 4 ; Toll-Like Receptor 4 - metabolism ; transcription factor NF-kappa B ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2015-04, Vol.112 (15), p.4731-4736</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3892-905131e3932576e987401c9ef66463e45f0201790787bf3cc7a737ece989dac83</citedby><cites>FETCH-LOGICAL-c3892-905131e3932576e987401c9ef66463e45f0201790787bf3cc7a737ece989dac83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/112/15.cover.gif</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403188/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403188/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25825741$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xianjing</creatorcontrib><creatorcontrib>Wang, Duowei</creatorcontrib><creatorcontrib>Chen, Zhen</creatorcontrib><creatorcontrib>Lu, Ermei</creatorcontrib><creatorcontrib>Wang, Zhuo</creatorcontrib><creatorcontrib>Duan, Jingjing</creatorcontrib><creatorcontrib>Tian, Wei</creatorcontrib><creatorcontrib>Wang, Yun</creatorcontrib><creatorcontrib>You, Linjun</creatorcontrib><creatorcontrib>Zou, Yulian</creatorcontrib><creatorcontrib>Cheng, Yan</creatorcontrib><creatorcontrib>Zhu, Qingyi</creatorcontrib><creatorcontrib>Wan, Xiaojian</creatorcontrib><creatorcontrib>Xi, Tao</creatorcontrib><creatorcontrib>Jiang, Meisheng</creatorcontrib><creatorcontrib>Han, Yuyuan</creatorcontrib><creatorcontrib>Cao, Cong</creatorcontrib><creatorcontrib>Birnbaumer, Lutz</creatorcontrib><creatorcontrib>Chu, Wen-Ming</creatorcontrib><creatorcontrib>Yang, Yong</creatorcontrib><title>Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Significance In this study, we demonstrate that guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) regulate the downstream signaling pathways of Toll-like receptor 4 (TLR4). We show that Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling and NF-κB activation. Besides, Gα ᵢ₁/₃ act at both the plasma membrane and the endosome levels and are involved in TLR4 endocytosis. Furthermore, Gα ᵢ₁/₃ participated in the induction of M1 polarization of macrophages, and their decreased expression contributed to LPS tolerance. Thus, Gα ᵢ₁/₃ are important in controlling inflammation.
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gα ᵢ₁/₃ deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gα ᵢ₁/₃ knockdown in bone marrow-derived macrophage cells (Gα ᵢ₁/₃ KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gα ᵢ₁/₃ deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gα ᵢ₁/₃ were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gα ᵢ₁/₃ can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Blotting, Western</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>endocytosis</subject><subject>Endocytosis - drug effects</subject><subject>G-proteins</subject><subject>GTP-Binding Protein alpha Subunits, Gi-Go - genetics</subject><subject>GTP-Binding Protein alpha Subunits, Gi-Go - metabolism</subject><subject>Humans</subject><subject>inflammation</subject><subject>Interleukin-12 - metabolism</subject><subject>Interleukin-6 - metabolism</subject><subject>Lipopolysaccharide Receptors - genetics</subject><subject>Lipopolysaccharide Receptors - metabolism</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Macrophages, Peritoneal - drug effects</subject><subject>Macrophages, Peritoneal - metabolism</subject><subject>Mice, 129 Strain</subject><subject>Mice, Knockout</subject><subject>Microscopy, Confocal</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>plasma membrane</subject><subject>Protein Binding - drug effects</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>signal transduction</subject><subject>Survival Analysis</subject><subject>Toll-like receptor 4</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>transcription factor NF-kappa B</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFu1DAQhi0EokvhzA1y5JJ2JnZi-4KEFlqQKnFoe7ZmvU4alMTBziLKDfomvAEHXoN3gCfB0W6XcrJsf_PNaH7GniIcIUh-PA4Uj7AELqVGLO6xBYLGvBIa7rMFQCFzJQpxwB7F-AEAdKngITsoSlWUUuCC1ae_fvz--f3Pt68ZDevs9naTBddsOppc1pMNfryixmWj7yi0X2hq_ZCtrrPah74dmowy6_uxc5_TOUzUDvPj8jWKrZNW-Jg9qKmL7snuPGSXJ28ulm_zs_en75avznLLlS5yDSVydFzzNF7ltJIC0GpXV5WouBNlDQWg1CCVXNXcWkmSS2cTqddkFT9kL7fecbPq3dq6YQrUmTG0PYVr46k1__8M7ZVp_CcjBHBUs-DFThD8x42Lk-nbaF3X0eD8JhpUwFN3IXhCj7do2k-MwdX7NghmTsfM6Zh_6aSKZ3en2_O3cSTg-Q6YK_c6LJLFCMnvEDV5Q01oo7k8TzupAJDrQij-F-GEo2M</recordid><startdate>20150414</startdate><enddate>20150414</enddate><creator>Li, Xianjing</creator><creator>Wang, Duowei</creator><creator>Chen, Zhen</creator><creator>Lu, Ermei</creator><creator>Wang, Zhuo</creator><creator>Duan, Jingjing</creator><creator>Tian, Wei</creator><creator>Wang, Yun</creator><creator>You, Linjun</creator><creator>Zou, Yulian</creator><creator>Cheng, Yan</creator><creator>Zhu, Qingyi</creator><creator>Wan, Xiaojian</creator><creator>Xi, Tao</creator><creator>Jiang, Meisheng</creator><creator>Han, Yuyuan</creator><creator>Cao, Cong</creator><creator>Birnbaumer, Lutz</creator><creator>Chu, Wen-Ming</creator><creator>Yang, Yong</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20150414</creationdate><title>Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1</title><author>Li, Xianjing ; Wang, Duowei ; Chen, Zhen ; Lu, Ermei ; Wang, Zhuo ; Duan, Jingjing ; Tian, Wei ; Wang, Yun ; You, Linjun ; Zou, Yulian ; Cheng, Yan ; Zhu, Qingyi ; Wan, Xiaojian ; Xi, Tao ; Jiang, Meisheng ; Han, Yuyuan ; Cao, Cong ; Birnbaumer, Lutz ; Chu, Wen-Ming ; Yang, Yong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3892-905131e3932576e987401c9ef66463e45f0201790787bf3cc7a737ece989dac83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Blotting, Western</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>endocytosis</topic><topic>Endocytosis - drug effects</topic><topic>G-proteins</topic><topic>GTP-Binding Protein alpha Subunits, Gi-Go - genetics</topic><topic>GTP-Binding Protein alpha Subunits, Gi-Go - metabolism</topic><topic>Humans</topic><topic>inflammation</topic><topic>Interleukin-12 - metabolism</topic><topic>Interleukin-6 - metabolism</topic><topic>Lipopolysaccharide Receptors - genetics</topic><topic>Lipopolysaccharide Receptors - metabolism</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Macrophages, Peritoneal - drug effects</topic><topic>Macrophages, Peritoneal - metabolism</topic><topic>Mice, 129 Strain</topic><topic>Mice, Knockout</topic><topic>Microscopy, Confocal</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>plasma membrane</topic><topic>Protein Binding - drug effects</topic><topic>Protein Subunits - genetics</topic><topic>Protein Subunits - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>signal transduction</topic><topic>Survival Analysis</topic><topic>Toll-like receptor 4</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>transcription factor NF-kappa B</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Xianjing</creatorcontrib><creatorcontrib>Wang, Duowei</creatorcontrib><creatorcontrib>Chen, Zhen</creatorcontrib><creatorcontrib>Lu, Ermei</creatorcontrib><creatorcontrib>Wang, Zhuo</creatorcontrib><creatorcontrib>Duan, Jingjing</creatorcontrib><creatorcontrib>Tian, Wei</creatorcontrib><creatorcontrib>Wang, Yun</creatorcontrib><creatorcontrib>You, Linjun</creatorcontrib><creatorcontrib>Zou, Yulian</creatorcontrib><creatorcontrib>Cheng, Yan</creatorcontrib><creatorcontrib>Zhu, Qingyi</creatorcontrib><creatorcontrib>Wan, Xiaojian</creatorcontrib><creatorcontrib>Xi, Tao</creatorcontrib><creatorcontrib>Jiang, Meisheng</creatorcontrib><creatorcontrib>Han, Yuyuan</creatorcontrib><creatorcontrib>Cao, Cong</creatorcontrib><creatorcontrib>Birnbaumer, Lutz</creatorcontrib><creatorcontrib>Chu, Wen-Ming</creatorcontrib><creatorcontrib>Yang, Yong</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xianjing</au><au>Wang, Duowei</au><au>Chen, Zhen</au><au>Lu, Ermei</au><au>Wang, Zhuo</au><au>Duan, Jingjing</au><au>Tian, Wei</au><au>Wang, Yun</au><au>You, Linjun</au><au>Zou, Yulian</au><au>Cheng, Yan</au><au>Zhu, Qingyi</au><au>Wan, Xiaojian</au><au>Xi, Tao</au><au>Jiang, Meisheng</au><au>Han, Yuyuan</au><au>Cao, Cong</au><au>Birnbaumer, Lutz</au><au>Chu, Wen-Ming</au><au>Yang, Yong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2015-04-14</date><risdate>2015</risdate><volume>112</volume><issue>15</issue><spage>4731</spage><epage>4736</epage><pages>4731-4736</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Significance In this study, we demonstrate that guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) regulate the downstream signaling pathways of Toll-like receptor 4 (TLR4). We show that Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling and NF-κB activation. Besides, Gα ᵢ₁/₃ act at both the plasma membrane and the endosome levels and are involved in TLR4 endocytosis. Furthermore, Gα ᵢ₁/₃ participated in the induction of M1 polarization of macrophages, and their decreased expression contributed to LPS tolerance. Thus, Gα ᵢ₁/₃ are important in controlling inflammation.
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gα ᵢ₁/₃) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gα ᵢ₁/₃ form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gα ᵢ₁/₃ deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gα ᵢ₁/₃ knockdown in bone marrow-derived macrophage cells (Gα ᵢ₁/₃ KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gα ᵢ₁/₃ deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gα ᵢ₁/₃ were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gα ᵢ₁/₃ can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>25825741</pmid><doi>10.1073/pnas.1503779112</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2015-04, Vol.112 (15), p.4731-4736 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_pnas_primary_112_15_4731 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Adaptor Proteins, Signal Transducing Animals Biological Sciences Blotting, Western Cell Line, Tumor Cells, Cultured endocytosis Endocytosis - drug effects G-proteins GTP-Binding Protein alpha Subunits, Gi-Go - genetics GTP-Binding Protein alpha Subunits, Gi-Go - metabolism Humans inflammation Interleukin-12 - metabolism Interleukin-6 - metabolism Lipopolysaccharide Receptors - genetics Lipopolysaccharide Receptors - metabolism Lipopolysaccharides - pharmacology macrophages Macrophages - drug effects Macrophages - metabolism Macrophages, Peritoneal - drug effects Macrophages, Peritoneal - metabolism Mice, 129 Strain Mice, Knockout Microscopy, Confocal Mitogen-Activated Protein Kinases - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism plasma membrane Protein Binding - drug effects Protein Subunits - genetics Protein Subunits - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA Interference signal transduction Survival Analysis Toll-like receptor 4 Toll-Like Receptor 4 - metabolism transcription factor NF-kappa B Tumor Necrosis Factor-alpha - metabolism |
| title | Gαᵢ₁ and Gαᵢ₃ regulate macrophage polarization by forming a complex containing CD14 and Gab1 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T14%3A12%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pnas_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=G%CE%B1%E1%B5%A2%E2%82%81%20and%20G%CE%B1%E1%B5%A2%E2%82%83%20regulate%20macrophage%20polarization%20by%20forming%20a%20complex%20containing%20CD14%20and%20Gab1&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Li,%20Xianjing&rft.date=2015-04-14&rft.volume=112&rft.issue=15&rft.spage=4731&rft.epage=4736&rft.pages=4731-4736&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1503779112&rft_dat=%3Cproquest_pnas_%3E1803078443%3C/proquest_pnas_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1803078443&rft_id=info:pmid/25825741&rfr_iscdi=true |