The MIIC where the receptor can bind DNA containing complexes captured by the endocytosed BCR. Analysis of BCR and TLR9 endocytic trafficking in anergic B cells, in which the trafficking of both INCB28060 supply receptors is aberrant, indicates that entry of the BCR and TLR9 into late endosomes is coordinated and that both receptors enter on common transport vesicles. Presumably, this facilitates the transfer of BCR captured ligands to the TLRs. Work from several laboratories has provided a general model for how endocytosed receptor complexes are sorted through early endosomes and delivered into late endosomal multivesicular bodies. Central to this model is the monoubiquitination of receptors and the recognition of these ubiquitins by a protein complex containing Hrs, Eps15 and STAM. ESCRT-0 engaged receptors are retained within the endosomal pathway while unbound receptors recycle to the cell surface. Successive recruitment of the multimeric complexes ESCRT-I, ESCRT-II, and ESCRT-III target receptors to late endosomes. These receptors are then sorted into intraluminal multivesicular bodies where they are degraded. While the ESCRT complexes constitute the core machinery for the delivery of receptors to late endosomes, several other molecular complexes are involved in facilitating and regulating ESCRT-mediated endocytic transit. Previously, we have demonstrated that the BCR subunit Igb is ubiquitinated and that this is required for sorting to late endosomes. Normal receptor ubiquitination required Itch, a member of the Nedd4 family of E3s. This is in apparent contrast to the T cell receptor, and other receptors, where recruitment of the Casitas B-lineage Lymphoma E3s to the tyrosine phosphorylated receptor induce ubiquitination. We now report that Cbl-b is also required for BCR endocytic trafficking, and that it contributes to receptor ubiquitination following receptor stimulation. However, Cbl-b ligase activity is dispensible for BCR endocytic trafficking. Rather, Cbl-b provides a necessary scaffolding function that is dependent upon the carboxyterminal tail. Surprisingly, transit of TLR9 into late endosomes was also dependent upon Cbl-b. These and other findings demonstrate a unique, unexpected, and functionally important role for Cbl-b in directing the delivery of both the BCR and TLR9 to late endosomes. Herein, we demonstrate that recruitment of Cbl-b to the BCR is necessary for both clustering the BCR on the cell surface and for guiding internalized BCRs into late endosomes. This activity of Cbl-b was unique and could not be supplanted by c-Cbl. Furthermore, Cbl-b was required for TLR9 entry into late endosomes and for activation of TLR9 by BCR captured ligands. In the absence of Cbl-b, the BCR and TLR9 became sequestered together within terminal lysosomes. These data indicate that Cbl-b plays an important role in coupling adaptive and innate immune signaling responses in B lymphocytes.