The Syk-binding Ubiquitin Ligase c-Cbl Mediates Signaling-dependent B Cell Receptor Ubiquitination and B Cell Receptor-mediated Antigen Processing and Presentation

Abstract

Background: c-Cbl associates with various signaling molecules to regulate diverse signaling networks via ubiquitination of receptors and/or protein tyrosine kinases. Results: c-Cbl drives ubiquitin-dependent Ag⅐BCR trafficking to MIIC and BCR-mediated antigen processing and presentation. Conclusion: c-Cbl directs BCR-mediated antigen processing and presentation. Significance: c-Cbl coordinates antigen-induced BCR signaling and rapid BCR-mediated antigen processing and presentation to drive a strong humoral immune response.

Role of X-Chromosome encoded miRNAs in Autoimmunity: Suppressing the suppressor and Female Predisposition

“…CBL and CBLB have also been shown to interact with BCR signaling molecules and downregulate BCR signaling pathways [45,46]. In addition, CBL mediated ubiquitylation controls BCRmediated antigen processing and presentation [47].…”

Antigen-B Cell Receptor Complexes Associate with Intracellular major histocompatibility complex (MHC) Class II Molecules

“…6). At doses of src kinase inhibitor known to block BCR signaling and signaling-dependent BCR ubiquitination (21,22), we failed to observe a difference in the kinetics of Ag-BCR-class II complex formation. This finding suggests that the association of internalized Ag-BCR com- plexes and class II molecules is not dependent on signaling-dependent BCR ubiquitination.…”

“…Previous studies have established that accelerated conversion of Ag-BCR complexes to derivative peptide-class II complexes is promoted by the signaling-dependent ubiquitination of lipid raft-resident Ag-BCR complexes (21)(22)(23). To determine whether signaling-dependent BCR ubiquitination is necessary for association of internalized Ag-BCR complexes with class II molecules, the impact of blocking src family kinase-dependent BCR signaling (the first step in the BCR signaling and ubiquitination pathways) on the kinetics of Ag-BCR-class II complex formation was determined (Fig.…”

Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

“…BCRs that are internalized at a low rate in the absence of antigen are mostly recycled back to the cell surface. However, antigen-induced crosslinking of the BCRs and subsequent signaling increase not only the rate of internalization but also the rate of sorting into late endosomes (Aluvihare et al 1997), which requires ubiquitination of the BCR by c-Cbl (Katkere et al 2012;Zhang et al 2007) and Cbl-b (Veselits et al 2014). As discussed above, the absence of both of these ubiquitin ligases blocks BCR internalization at the plasma membrane.…”

“…As discussed above, the absence of both of these ubiquitin ligases blocks BCR internalization at the plasma membrane. In the absence of either c-Cbl or Cbl-b, BCR-antigen complexes are still internalized, but do not traffic to late endosomes (Katkere et al 2012;Veselits et al 2014).…”