Ubiquitin Ligases as Key Elements for the Modulation of the Immune Response: An Insight in the Pathogenesis of Autoimmunity
Mariana Diaz Zamudio,
Ubiquitin ligases are the substrate specific elements of the ubiquitination system, which comprises a posttranslational mechanism by which the immune response can be modulated, setting the tune for the TCR activation. Proteolysis dependent and independent mechanisms have been implicated. Ubiquitin ligases have been proven as key modulators of central and peripheral tolerance, involving the regulation of anergy and regulatory T cells. These enzymes involve a complex regulatory network designed to maintain an active surveillance system. Cbl-b, GRAIL and Itch are the main E3 ligases, considered as negative regulators of the immune response as part of the anergy induced genetic program. Recently, other ubiquitin ligases have been related to autoimmune pathologies such as Roquin and Ro52. Other key signalling pathways for the immune response, such as the NF-κB and TGF-β signalling are prone to be modulated by these ubiquitin ligases. Diverse processes have been implicated in the broad mechanisms of modulation of the immune response by these ubiquitin ligases, among them, the setting for TCR responsiveness, T cell differentiation, regulation of activation and costimulatory molecules as well as of inflammatory pathways are the best well characterized. The defective expression of some of these ubiquitin ligases has been related to the development of autoimmune disease, in experimental murine and human models. Most of the evidence points towards the physiopathogenic role of ubiquitin ligases, primarily Cbl-b in systemic (SLE) and organ-specific (type 1 Diabetes Mellitus and multiple sclerosis) autoimmune diseases.
Keywords: Autoimmunity, Cbl-b, GRAIL, itch, roquin, Ro52, tolerance, ubiquitin ligases
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