Abstract
Non-agouti-lethal 18H (a18H) mice are dark agouti with black pinna hairs. What makes these mice unique is that they develop a spectrum of immunological diseases not seen in other agouti mutant mice1. On the JU/Ct background, a18H mice develop an inflammatory disease of the large intestine. On the C57BL/6J background, they develop a fatal disease characterized by pulmonary chronic interstitial inflammation and alveolar proteinosis, inflammation of the glandular stomach and skin resulting in scarring due to constant itching, and hyperpla-sia of lymphoid cells, haematopoietic cells and the forestomach epithelium. Previous studies suggested that the a18H mutation results from a paracentric inversion that affects two loci: agouti and another, as yet unidentified locus designated itchy (the provisional gene symbol is Itch), that is responsible for the immunological phenotype of a18H mice1. Here we confirm that a18H results from an inversion and show that Itch encodes a novel E3 ubiquitin protein ligase, a protein involved in ubiqui-tin-mediated protein degradation. Our results indicate that ubiquitin-dependent proteolysis is an important mediator of the immune response in vivo and provide evidence for Itch's role in inflammation and the regulation of epithelial and haematopoietic cell growth.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hustad, C.M. et al. Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics 140, 255–265 (1995).
Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).
Scheffner, M., Nuber, U. & Huibregtse, J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 375, 81–83 (1995).
Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Adds Res. 15, 8125–8148 (1987).
Huibregtse, J.M., Scheffner, M. & Howley, P.M. Cloning and expression of the cDNA for E6-Ap, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol. Cell. Biol. 13, 775–784 (1993).
Huibregtse, J.M., Scheffner, M., Beaudenon, S. & Howley, P.M. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc. Natal. Acad. Sci. USA 92, 2563–2567 (1995).
Sudol, M. The WW module competes with the SH3 domain? Trends Biochem. Sci. 21, 161–163 (1996).
Daveltov, B.A. & Sudhof, T.C. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J. Biol. Chem. 268, 26386–26390 (1993).
Vrieling, H.D., Duhl, M.J., Millar, S.E., Miller, K.A. & Barsh, G.S. Differences in dorsal and ventral pigmentation results from regional expression of the mouse agouti gene. Proc. Natal. Acad. Sci. USA 91, 170–178 (1994).
Green, M.C. & Schultz, L.D., Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J. Hered. 66, 250–258 (1975).
Sidman, C.L., Shultz, L.D. & Unanue, E.R. The mouse mutant “motheaten.” I. Development of lymphocyte populations. J. Immunol. 121, 2392–2398 (1978).
Ward, J.M. Pulmonary pathology of the motheaten mouse. Vet. Pathol. 15, 170–178 (1978).
Shultz, L.D. et al. Mutations at the murine motheaten locus are within the haematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454 (1993).
Tsui, H.W., Siminovitch, K.A., De Souza, L., & Tsui, F.W.L. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124–129 (1993).
Jiao, H. et al. Macrophages from motheaten and viable motheaten mutant mice show increased proliferative responses to GM-CSF: Detection of potential HCP substrates in GM-CSF signal transduction. Exp. Haematol. 25, 592–600 (1997).
Piao, X., Paulson, R., van der Geer, P., Pawson, T. & Bernstein, A. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natal. Acad. Sci. USA 93, 14665–14669 (1996).
David, M., Chen, H.E., Goelz, S., Larner, A.C. & Neel, B.G. Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol. Cell. Biol. 15, 7050–7058 (1995).
Lee, F.S., Hagler, J., Chen, Z.J. & Maniatis, T. Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88, 213–222 (1997).
Miyazawa, K. et al. Ligand-dependent polyubiquitination of c-fc/tgene product: a possible mechanism of receptor down modulation in M107e cells. Blood 83, 137–145 (1994).
Mori, S., Heldin, C.-H. & Claesson-Welsh, L. Ligand-induced polyubiquitination of the platelet-derived growth factor (3-receptor plays a negative regulatory role in its mitogenic signaling. J. Biol. Chem. 268, 577–583 (1992).
Mori, S., Claesson-Welsh, L., Okuyama, Y. & Saito, Y. Ligand-induced polyubiquitination of receptor tyrosine kinases. Biochem. Biophys. Rec. Comm. 213, 32–39 (1995).
Mori, S., Tanaka, K., Omura, S. & Saito, Y. Degradation process of ligand-stimulated platelet-derived growth factor receptor involves ubiquitin-proteasome proteolytic pathway. J. Biol. Chem. 270, 29447–29452 (1995).
Cattanach, B.M., Lyon, M.F., Peters, J. & Searle, A.G. Agouti locus mutations at Harwell. Mouse News Lett. 77, 123–125 (1987).
Gish, W. & States, D.J. Identification of protein coding regions by database similarity search. Nature Genet. 3, 266–272 (1993).
Perry, W.L., Hustad, C.M., Swing, D.A., Jenkins, N.A. & Copeland, N.G. A transgenic mouse assay for agouti protein activity. Genetics 140, 267–274 (1995).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Perry, W., Hustad, C., Swing, D. et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 18, 143–146 (1998). https://doi.org/10.1038/ng0298-143
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0298-143
This article is cited by
-
Silencing Itch in human peripheral blood monocytes promotes their differentiation into osteoclasts
Molecular Biology Reports (2022)
-
Adaptors as the regulators of HECT ubiquitin ligases
Cell Death & Differentiation (2021)
-
Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies
Discover Oncology (2021)
-
Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration
Cell Death & Disease (2020)
-
Cir-ITCH inhibits gastric cancer migration, invasion and proliferation by regulating the Wnt/β-catenin pathway
Scientific Reports (2020)