Two Families of GTPases Dominate the Complex Cellular Response to IFN-γ

Abstract

Abstract IFN-γ induces a number of cellular programs functional in innate and adaptive resistance to infectious pathogens. It has recently become clear that the complete cellular response to IFN-γ is extraordinarily complex, with >500 genes (i.e., ∼0.5% of the genome) activated. We made suppression-subtractive hybridization differential libraries from IFN-γ-stimulated primary mouse embryonic fibroblasts and from a mouse macrophage cell line, ANA-1, in each case with reference to unstimulated cells. Of ∼250 clones sequenced at random from the two libraries, >35% were representatives of one or the other of two small unrelated families of GTPases, the 65-kDa and 47-kDa families. These families dominate the IFN-γ-induced response in both cell types. We report here the full-length sequences of one new 65-kDa and two new 47-kDa family members. The 65-kDa family members are under transcriptional control of IRF-1, whereas the 47-kDa family members are inducible in embryonic fibroblasts from IRF-1−/− mice. Members of both GTPase families are strongly up-regulated in livers of wild-type mice infected with the pathogenic bacterium, Listeria monocytogenes, but not in IFN-γR0/0 mice. These GTPases appear to be dedicated to the IFN-γ response, since resting levels are negligible and since neither family shows any significant relationship to any other described family of GTPases. Understanding the role of these GTPases in IFN-γ-mediated resistance against pathogens is the task for the future.