This information is current as Ligase Cbl Signaling by Inhibiting the E 3 Ubiquitin Plasmacytoid Dendritic Cell Receptor CD 2 AP / SHIP 1 Complex Positively Regulates

The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor Fc « R1 g 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/Fc « R1 g receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/Fc « R1 g -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 Fc « R1 g 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/Fc « R1 g complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/Fc « R1 g complex. Therefore, CD2AP positively regulates BDCA2/Fc « R1 g signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl. The Journal

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