The Role of Mammalian Actin Binding Protein 1 in Coupling BCR Signaling and Antigen Transport Functions

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The B cell receptor (BCR) serves as both signal-transducer and antigen-transporter. Binding of antigens to the BCR induces signaling cascades and antigen-processing and presentation, two essential cellular events for B cell activation. BCR-initiated signaling increases BCR-mediated antigen-processing efficiency by increasing the rate and specificity of antigen transport. Previous studies showed a critical role for the actin cytoskeleton in these two processes. Here I found that actin-binding protein 1 (Abp1/HIP-55/SH3P7) functioned as an actin-binding adaptor protein, coupling BCR signaling and antigen-processing pathways with the actin cytoskeleton. Gene knockout of Abp1 and over-expression of the SH3 domain of Abp1 inhibited BCR-mediated antigen internalization, consequently reducing the rate of antigen transport to processing compartments and the efficiency of BCR-mediated antigen-processing and presentation. BCR activation induced tyrosine phosphorylation of Abp1 and translocation of both Abp1 and dynamin 2 from the cytoplasm to the plasma membrane, where they colocalized with the BCR and cortical F-actin. The inhibitory effect of a dynamin PRD deletion mutant on the recruitment of Abp1 to the plasma membrane and the internalization of the BCR, co-immunoprecipitation of dynamin with Abp1, and co-precipitation of Abp1 with GST fusion of the dynamin PRD, demonstrate the interaction of Abp1 with dynamin 2. In addition to its role in antigen transport and processing, Abp1 is also important for BCR signal transduction. Splenic B cells from Abp1 knockout mice and A20 B cell line with Abp1 knockdown displayed higher levels of protein tyrosine phosphorylation after BCR crosslinking when compared with wild type mice. BCR-triggered ERK phosphorylation in Abp1-deficient splenic B cells occurred sooner and for a much shorter duration than the wild type B cells, while both Abp1 knockout and knockdown significantly reduced BCR-induced phosphorylation of JNK. These results demonstrate that the BCR regulates the function of Abp1 by inducing Abp1 phosphorylation and actin cytoskeleton rearrangement, and that Abp1 facilitates BCR-mediated antigen-processing by simultaneously interacting with dynamin and the actin cytoskeleton. My results further suggest a negative regulatory role for Abp1 in BCR signal transduction.