Regulation of immune system development and function by Cbl‐mediated ubiquitination

Abstract

Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.

Targeting ubiquitin signaling for cancer immunotherapy

“…The TCR-proximal signaling events are tightly controlled by ubiquitination, which mediates degradation or functional inactivation of key components of the TCR signaling pathway, such as CD3ζ, ZAP70, phospholipase C gamma 1 (PLCγ1), PI3 kinase (PI3K), and protein kinase C theta (PKCθ). 5 A well-characterized E3 ligase involved in the regulation of TCR signaling is Cbl-b, which targets PI3K and the guanine nucleotide exchange factor VAV and is crucial for maintaining T cell tolerance and preventing autoimmunity 69,70 (Fig. 2).…”

Roles of Ubiquitination and Deubiquitination in Regulating Dendritic Cell Maturation and Function

“…While a deficiency of Cbl‐b alone exhibits no obvious effects on DC development and function ( 41 ), it has been reported that mice which a double ablation of c-Cbl and Cbl-b in DCs results in the development of severe liver inflammation ( 42 ). Cbl mutant mice display significantly increased cDC1 in the peripheral lymphoid organs and liver, which exhibits a hyperactivated phenotype and mediates the systemic activation of T and B cells.…”

“…Further studies have shown that Cbls promote FMS-like tyrosine kinase 3 (FLT3) signaling via the ubiquitination of FLT3. This research suggests that both c-Cbl and Cbl-b–mediated ubiquitination hold the key for DC subset homeostasis and immune quiescence under steady‐state conditions, implying that c-Cbl and Cbl-b may have the potential to be therapeutic targets for the treatment of DC-mediated liver inflammation ( 42 ).…”

Current Challenges in Vaccinology

“…Genetics has expanded far beyond the simple nucleic acid sequence of a given organism. While it primarily deals with individual genes, it also includes the myriad regulatory mechanisms that control gene expression (16)(17)(18)(19)(20)(21)(22). Similarly, genomics has also expanded in scope to include the comprehensive characterization of gene expression, regulation, interdependency, pre-and post-transcriptional modifications, gene editing, epistasis, complementarity, pleiotropy, and other complex interactions (23).…”