CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl
The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcεR1γ to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced auto...
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| Veröffentlicht in: | The Journal of immunology (1950) 2012-07, Vol.189 (2), p.786-792 |
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| container_title | The Journal of immunology (1950) |
| container_volume | 189 |
| creator | Bao, Musheng Hanabuchi, Shino Facchinetti, Valeria Du, Qiumei Bover, Laura Plumas, Joel Chaperot, Laurence Cao, Wei Qin, Jun Sun, Shao-Cong Liu, Yong-Jun |
| description | The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcεR1γ to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcεR1γ receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcεR1γ-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcεR1γ that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcεR1γ complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcεR1γ complex. Therefore, CD2AP positively regulates BDCA2/FcεR1γ signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl. |
| doi_str_mv | 10.4049/jimmunol.1200887 |
| format | Article |
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BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcεR1γ receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcεR1γ-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcεR1γ that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcεR1γ complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcεR1γ complex. Therefore, CD2AP positively regulates BDCA2/FcεR1γ signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1200887</identifier><identifier>PMID: 22706086</identifier><language>eng</language><publisher>United States</publisher><subject>Adaptor Proteins, Signal Transducing - physiology ; Cells, Cultured ; Cross-Linking Reagents - metabolism ; Cytoskeletal Proteins - physiology ; Dendritic Cells - enzymology ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; HEK293 Cells ; Humans ; Inositol Polyphosphate 5-Phosphatases ; Lectins, C-Type - physiology ; Membrane Glycoproteins - physiology ; Multiprotein Complexes - physiology ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ; Phosphoric Monoester Hydrolases - physiology ; Proto-Oncogene Proteins c-cbl - antagonists & inhibitors ; Proto-Oncogene Proteins c-cbl - metabolism ; Receptors, Immunologic - physiology ; Signal Transduction - immunology ; Up-Regulation - immunology</subject><ispartof>The Journal of immunology (1950), 2012-07, Vol.189 (2), p.786-792</ispartof><rights>Copyright © 2012 by The American Association of Immunologists, Inc. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c495t-acebb19bfa38362e39dec929e70f18358f3ad7b9d613274f1cbada95a3a2ff703</citedby><cites>FETCH-LOGICAL-c495t-acebb19bfa38362e39dec929e70f18358f3ad7b9d613274f1cbada95a3a2ff703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22706086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bao, Musheng</creatorcontrib><creatorcontrib>Hanabuchi, Shino</creatorcontrib><creatorcontrib>Facchinetti, Valeria</creatorcontrib><creatorcontrib>Du, Qiumei</creatorcontrib><creatorcontrib>Bover, Laura</creatorcontrib><creatorcontrib>Plumas, Joel</creatorcontrib><creatorcontrib>Chaperot, Laurence</creatorcontrib><creatorcontrib>Cao, Wei</creatorcontrib><creatorcontrib>Qin, Jun</creatorcontrib><creatorcontrib>Sun, Shao-Cong</creatorcontrib><creatorcontrib>Liu, Yong-Jun</creatorcontrib><title>CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcεR1γ to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcεR1γ receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcεR1γ-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcεR1γ that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcεR1γ complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcεR1γ complex. Therefore, CD2AP positively regulates BDCA2/FcεR1γ signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl.</description><subject>Adaptor Proteins, Signal Transducing - physiology</subject><subject>Cells, Cultured</subject><subject>Cross-Linking Reagents - metabolism</subject><subject>Cytoskeletal Proteins - physiology</subject><subject>Dendritic Cells - enzymology</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Inositol Polyphosphate 5-Phosphatases</subject><subject>Lectins, C-Type - physiology</subject><subject>Membrane Glycoproteins - physiology</subject><subject>Multiprotein Complexes - physiology</subject><subject>Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases</subject><subject>Phosphoric Monoester Hydrolases - physiology</subject><subject>Proto-Oncogene Proteins c-cbl - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-cbl - metabolism</subject><subject>Receptors, Immunologic - physiology</subject><subject>Signal Transduction - immunology</subject><subject>Up-Regulation - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtP3DAURq2Kqgy0e1aVl2wCfiROvKmEprQgIRWpsLZs5yZj5MTBTlBn2X9ejxgQrLry69zPvj4InVByVpJSnj-4YVjG4M8oI6Rp6g9oRauKFEIQcYBWhDBW0FrUh-gopQdCiCCs_IQOGavztBEr9Hf9nV3cnv--ur6l2IZh8vAHTyG52T2B3-II_eL1DAlPXqdB2-0cXItbGNuYGYsteJ8pC9McIk6uH7V3Y4_NFrtx40yG8mreAL7keDHucdntYO96nQCvjf-MPnbaJ_iyH4_R_Y_Lu_VVcfPr5_X64qawpazmQlswhkrTad5wwYDLFqxkEmrS0YZXTcd1WxvZCspZXXbUGt1qWWmuWdfVhB-jb8-502IGaC2Mc9ReTdENOm5V0E69PxndRvXhSXEhKl6xHHC6D4jhcYE0q8GlXft6hLAklX-e5svLhv8fzRp4RbkUGSXPqI0hpQjd64soUTvJ6kWy2kvOJV_fdvJa8GKV_wPWUqhB</recordid><startdate>20120715</startdate><enddate>20120715</enddate><creator>Bao, Musheng</creator><creator>Hanabuchi, Shino</creator><creator>Facchinetti, Valeria</creator><creator>Du, Qiumei</creator><creator>Bover, Laura</creator><creator>Plumas, Joel</creator><creator>Chaperot, Laurence</creator><creator>Cao, Wei</creator><creator>Qin, Jun</creator><creator>Sun, Shao-Cong</creator><creator>Liu, Yong-Jun</creator><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><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20120715</creationdate><title>CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl</title><author>Bao, Musheng ; Hanabuchi, Shino ; Facchinetti, Valeria ; Du, Qiumei ; Bover, Laura ; Plumas, Joel ; Chaperot, Laurence ; Cao, Wei ; Qin, Jun ; Sun, Shao-Cong ; Liu, Yong-Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c495t-acebb19bfa38362e39dec929e70f18358f3ad7b9d613274f1cbada95a3a2ff703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptor Proteins, Signal Transducing - physiology</topic><topic>Cells, Cultured</topic><topic>Cross-Linking Reagents - metabolism</topic><topic>Cytoskeletal Proteins - physiology</topic><topic>Dendritic Cells - enzymology</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Inositol Polyphosphate 5-Phosphatases</topic><topic>Lectins, C-Type - physiology</topic><topic>Membrane Glycoproteins - physiology</topic><topic>Multiprotein Complexes - physiology</topic><topic>Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases</topic><topic>Phosphoric Monoester Hydrolases - physiology</topic><topic>Proto-Oncogene Proteins c-cbl - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-cbl - metabolism</topic><topic>Receptors, Immunologic - physiology</topic><topic>Signal Transduction - immunology</topic><topic>Up-Regulation - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bao, Musheng</creatorcontrib><creatorcontrib>Hanabuchi, Shino</creatorcontrib><creatorcontrib>Facchinetti, Valeria</creatorcontrib><creatorcontrib>Du, Qiumei</creatorcontrib><creatorcontrib>Bover, Laura</creatorcontrib><creatorcontrib>Plumas, Joel</creatorcontrib><creatorcontrib>Chaperot, Laurence</creatorcontrib><creatorcontrib>Cao, Wei</creatorcontrib><creatorcontrib>Qin, Jun</creatorcontrib><creatorcontrib>Sun, Shao-Cong</creatorcontrib><creatorcontrib>Liu, Yong-Jun</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><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bao, Musheng</au><au>Hanabuchi, Shino</au><au>Facchinetti, Valeria</au><au>Du, Qiumei</au><au>Bover, Laura</au><au>Plumas, Joel</au><au>Chaperot, Laurence</au><au>Cao, Wei</au><au>Qin, Jun</au><au>Sun, Shao-Cong</au><au>Liu, Yong-Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2012-07-15</date><risdate>2012</risdate><volume>189</volume><issue>2</issue><spage>786</spage><epage>792</epage><pages>786-792</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcεR1γ to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcεR1γ receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcεR1γ-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcεR1γ that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcεR1γ complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcεR1γ complex. Therefore, CD2AP positively regulates BDCA2/FcεR1γ signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl.</abstract><cop>United States</cop><pmid>22706086</pmid><doi>10.4049/jimmunol.1200887</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - physiology Cells, Cultured Cross-Linking Reagents - metabolism Cytoskeletal Proteins - physiology Dendritic Cells - enzymology Dendritic Cells - immunology Dendritic Cells - metabolism HEK293 Cells Humans Inositol Polyphosphate 5-Phosphatases Lectins, C-Type - physiology Membrane Glycoproteins - physiology Multiprotein Complexes - physiology Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphoric Monoester Hydrolases - physiology Proto-Oncogene Proteins c-cbl - antagonists & inhibitors Proto-Oncogene Proteins c-cbl - metabolism Receptors, Immunologic - physiology Signal Transduction - immunology Up-Regulation - immunology |
| title | CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl |
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