Deleted in Breast Cancer 1 Suppresses B Cell Activation through RelB and Is Regulated by IKK Phosphorylation.
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Alternative NF-B signaling is crucial for B cell activation and Ig production, and it is mainly regulated by the inhibitor of B kinase (IKK) regulatory complex. Dysregulation of alternative NF-B signaling in B cells could therefore lead to hyperactive B cells and Ig overproduction. In our previous, study we found that deleted in breast cancer 1 (DBC1) is a suppressor of the alternative NF-B pathway to attenuate B cell activation. In this study, we report that loss of DBC1 results in spontaneous overproduction of Ig in mice after 10 mo of age. Using a double mutant genetic model, we confirm that DBC1 suppresses B cell activation through RelB inhibition. At the molecular level, we show that DBC1 interacts with alternative NF-B members RelB and p52 through its leucine zipper domain. In addition, phosphorylation of DBC1 at its C terminus by IKK facilitates its interaction with RelB and IKK, indicating that DBC1-mediated suppression of alternative NF-B is regulated by IKK. Our results define the molecular mechanism of DBC1 inhibition of alternative NF-B activation in suppressing B cell activation.
