CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl.
CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl.
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DOI：
10.4049/jimmunol.1200887
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Liu YJ
中科院分区：
文献类型：
--
作者：
Bao M;Hanabuchi S;Facchinetti V;Du Q;Bover L;Plumas J;Chaperot L;Cao W;Qin J;Sun SC;Liu YJ
人浆细胞样树突状细胞（pDC）受体BDCA 2与接头FcεR1γ形成复合物，以激活ITAM信号级联。BDCA 2受体信号负调控pDC中TLR 7/9介导的1型IFN应答，这可能在控制自身DNA/RNA诱导的自身免疫中起关键作用。我们在这篇文章中报道了在人pDC中高表达的CD 2相关衔接蛋白（CD 2AP）正调控BDCA 2/FcεR1γ受体信号转导。通过免疫沉淀和质谱分析，我们发现CD 2AP与SHIP 1结合。CD 2AP或SHIP 1的敲低降低了BDCA 2/FcεR1γ介导的ITAM信号传导，并阻断了其对TLR 9介导的1型IFN产生的抑制。CD 2AP或SHIP 1的敲低也增强了E3泛素连接酶Cbl介导的Syk和FcεR1γ的泛素化和降解。这使我们发现，在BDCA 2交联后，CD 2AP/SHIP 1复合物与Cbl结合并抑制其E3泛素连接酶活性。在人原代pDC中，BDCA 2/FcεR1γ复合物的交联诱导CD 2AP/SHIP 1/Cbl复合物募集至pDC的质膜，在那里它与BDCA 2/FcεR1γ复合物共定位。因此，CD 2AP通过与SHIP 1形成复合物来抑制E3遍在蛋白连接酶Cbi，从而正向调节BDCA 2/FcεR1γ信号传导。
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.
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