Two families of GTPases dominate the complex cellular response to IFN-gamma

IFN-gamma induces a number of cellular programs functional in innate and ad aptive resistance to infectious pathogens. It has recently become clear tha t the complete cellular response to IFN-gamma is extraordinarily complex, w ith >500 genes (i.e., similar to 0.5% of the genome) activated. We made sup pression-subtractive hybridization differential libraries from IFN-gamma-st imulated primary mouse embryonic fibroblasts and from a mouse macrophage ce ll line, ANA-1, in each case with reference to unstimulated cells. Of simil ar to 250 clones sequenced at random from the two libraries, >35% were repr esentatives of one or the other of two small unrelated families of GTPases, the 65-kDa and 47-kDa families. These families dominate the IFN-gamma-indu ced response in both cell types. We report here the full-length sequences o f one new 65-kDa and two new 47-kDa family members, The 65-kDa family membe rs are under transcriptional control of IRF-1, whereas the 47-kDa family me mbers are inducible in embryonic fibroblasts from IRF-1(-/-) mice. Members of both GTPase families are strongly up-regulated in livers of wild-type mi ce infected with the pathogenic bacterium, Listeria monocytogenes, but not in IFN-gamma R-0/0 mice. These GTPases appear to be dedicated to the IFN-ga mma 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-gamma-mediated resistance against pathogens is the task for the future.