Ubiquitination system and autoimmunity: the bridge towards the modulation of the immune response.
The ubiquitination system comprises a highly specific and regulated post-translational mechanism by which the immune response can be modulated, setting the balance between immunity and tolerance. Proteolysis dependent and independent mechanisms have been implicated. Particularly, the role of ubiquitin ligases as modulators of central and peripheral tolerance has brought attention to this system as one of the key elements of 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 genetic program induced by the calcium/calcineurin pathway. Other key signaling pathways for the immune response, such as the NF-kappaB and TGF-beta signaling are prone to be modulated by these ubiquitin ligases. Diverse mechanisms have been implicated in the development of anergy associated to E3 ligases, among these, the setting for TCR responsiveness and repression of cytokine transcription are best well characterized. Also, a role as inductors of regulatory T cells has been evidenced for Cbl-b and GRAIL. The defective expression of some of these E3 ligases has been related to the development of autoimmune disease, in experimental murine and human models, remarking its possible pathogenic role.
Gómez-Martín
Diana
D
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan 14000, Mexico City, Mexico.
Díaz-Zamudio
Mariana
M
Alcocer-Varela
Jorge
J
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases