IDO MUTANTS CROSS RESISTANT TO TYPE-I INTERFERON RETAIN P91-DEPENDENTGENE INDUCTION

Genetic analyses of mutants have yielded valuable information about p9 1-associated interferon signal transduction. It was thus discovered th at p91 is an essential protein for the induction of both type I and ty pe II interferons, We previously reported the development of ME180 mut ants resistant to interferon-gamma because of a signaling defect resul ting in the loss of IDO induction, IDO does not respond to type I inte rferon despite an ISRE-like sequence upstream of the coding region, Ho wever, the IDO mutants were found to be cross-resistant to the growth- inhibitory effects of type I interferon, We therefore examined the eff ects of both types of interferon on interferon-stimulated gene mRNA ac cumulation and examined alterations in cellular protein introduced by the mutation, The induction of the p91-responsive gene 6-16 was not al tered in either of the mutants, and the early-induced gene IRF1 exhibi ted differences only in the kinetics of mRNA accumulation, The later i nduced gene, p68, also exhibited different kinetics, possibly reflecti ng the changes in IRF1, Immunoprecipitated p91 exhibited normal, inter feron-induced phosphorylation in both mutants, Two-dimensional gel ele ctrophoresis revealed that the mutant cells contained 20 peptides with altered biochemistry, These results suggest that IDO induction is con trolled by a distinct set of proteins not directly correlated with p91 activation,