Modulation of Immune Cell Functions by the E3 Ligase Cbl-b

Abstract

Maintenance of immunological tolerance is a critical hallmark of the immune system. Several signaling checkpoints necessary to balance activating and inhibitory input to immune cells have been described so far, among which the E3 ligase Cbl-b appears to be a central player. Cbl-b is expressed in all leukocyte subsets and regulates several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells. In most cases, Cbl-b negatively regulates activation signals through antigen or pattern recognition receptors and co-stimulatory molecules. In line with this function, cblb-deficient immune cells display lower activation thresholds and cblb knockout mice spontaneously develop autoimmunity and are highly susceptible to experimental autoimmunity. Interestingly, genetic association studies link CBLB-polymorphisms with autoimmunity also in humans. Vice versa, the increased activation potential of cblb-deficient cells renders them more potent to fight against malignancies or infections. Accordingly, several reports have shown that cblb knockout mice reject tumors, which mainly depends on cytotoxic T and NK cells. Thus, targeting Cbl-b may be an interesting strategy to enhance anti-cancer immunity. In this review, we summarize the findings on the molecular function of Cbl-b in different cell types and illustrate the potential of Cbl-b as target for immunomodulatory therapies.

Keywords: adoptive cell transfer; autoimmunity; cancer; immunotherapy; ubiquitination.

Figure 1

Functional domains of human Cbl and Cbl-like proteins. Three N-terminal regions [4-helical bundle (4H), EF-hand domain, and SH2 domain] constitute the tyrosine kinase binding (TKB) domain. Separated by a conserved linker (L) region follows a RING finger (RF) domain, which binds to E2 enzymes. The proline-rich sequence (PR) interacts with SH3 domains of various proteins involved in signaling and endocytosis. In the Cbl-like proteins, the order of the RF and TKB (here comprising a single C3H2 domain) is reversed. Only c-Cbl and Cbl-b contain an ubiquitin-associated domain (UBA) involved in binding and dimerization of ubiquitin. Several tyrosine residues in the L region and in the less conserved C-terminal half can be phosphorylated, resulting in conformational changes necessary for the ligase activity or interaction with SH2 domains of signaling proteins. Mutations associated with myeloproliferative disorders are located in the RF and L regions.

Figure 2

Interaction of Cbl-b with signaling pathways in diverse cells. Black receptors represent activating signaling pathways, red receptors inhibitory pathways. Black arrows indicate positive regulation, red bar-headed lines are representative for negative regulation. Dotted lines indicate secretion of proteins. Regulation of Cbl-b occurs not only at the transcriptional level but also by post-transcriptional mechanisms such as phosphorylation, degradation, or sequestration to specific protein complexes.