Two families of GTPases dominate the complex cellular response to IFN-gamma.
IFN-gamma 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-gamma is extraordinarily complex, with >500 genes (i.e., approximately 0.5% of the genome) activated. We made suppression-subtractive hybridization differential libraries from IFN-gamma-stimulated primary mouse embryonic fibroblasts and from a mouse macrophage cell line, ANA-1, in each case with reference to unstimulated cells. Of approximately 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-gamma-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-gammaR(0/0) mice. These GTPases appear to be dedicated to the IFN-gamma 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.
Boehm
U
U
Institute for Genetics, University of Cologne, Germany.
Guethlein
L
L
Klamp
T
T
Ozbek
K
K
Schaub
A
A
Fütterer
A
A
Pfeffer
K
K
Howard
J C
JC
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D020558:GTP Phosphohydrolases / Q000145:classification* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D015723:Gene Library; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D008088:Listeriosis / Q000276:immunology; D008099:Liver / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013382:Subtraction Technique; D014158:Transcription, Genetic; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D020558:GTP Phosphohydrolases; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D010750:Phosphoproteins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C494258:Irf1 protein, mouse; C491070:Iigp1 protein, mouse