Modification of proteins by the covalent attachment of ubiquitin chains has emerged as a major regulatory mechanism in cells. The enzymes that oppose this reaction, the deubiquitinating enzymes, are relatively poorly understood. Kayagaki et al. used an siRNA screen to search for deubiquitinating enzymes that influenced expression of the interferon I (IFN-I) gene in response to activation of Toll-like receptor 3 (TLR3), a central response by which the innate immune system detects viral RNAs and protects organisms from infection. They detected the deubiquitinase DUBA and went on to show that depletion of the enzyme enhanced the expression of IFN-1 and that overexpression of the protein inhibited the response. Other experiments identified the ubiquitin ligase TRAF3, which is required for induced expression of IFN-1, as a potential target of DUBA. Thus, DUBA restrains production of IFN-1, which, in excess, is associated with autoimmune disease.
N. Kayagaki, Q. Phung, S. Chan, R. Chaudhari, C. Quan, K. M. O'Rourke, M. Eby, E. Pietras, G. Cheng, J. F. Bazan, Z. Zhang, D. Arnott, V. M. Dixit, DUBA: A deubiquitinase that regulates type I interferon production. Science 318, 1628-1632 (2007). [Abstract] [Full Text]