Itchy mice: the identification of a new pathway for the development of autoimmunity.
Itchy mice possess a loss-of-function mutation in a HECT-domain-containing ubiquitin ligase (E3), Itch. Homozygous itchy mice develop a systemic and progressive autoimmune disease that proves lethal beginning at 6 months of age. Numerous targets of Itch-mediated ubiquitination have been identified, and some of these have defined physiological roles for Itch signaling in Tcell anergy and T cell differentiation. Studies of itchy mice have also allowed for the identification of a novel pathway involved in autoimmunity: noncanonical Notch signaling. In itchy mice carrying an activated Notch1 transgene, there are increased amounts of full-length Notch1, which can complex with p56(lck) and PI3K to activate a cell survival signal that is mediated by phospho-AKT. This, in turn, leads to a reduction in apoptosis in the thymus and may have consequences in T cell tolerance. A role for noncanonical Notch signaling in autoimmune disease is also supported by numerous mouse knockout studies, and suggests possible new therapeutic approaches for the treatment of autoimmune disease.
Matesic
L E
LE
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA. lmatesic@biol.sc.edu
Copeland
N G
NG
Jenkins
N A
NA
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000628:therapy; D051379:Mice; D009154:Mutation; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D051880:Receptors, Notch; D025801:Ubiquitin; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases