ATF3 regulates MCMV infection in mice by modulating IFN-gamma expression in natural killer cells.
Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with a cis-regulatory element of the IFN-gamma gene in natural killer (NK) cells, and that ATF3null NK cells show increased transcription and secretion of IFN-gamma. NK cell-derived IFN-gamma has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.
Rosenberger
Carrie M
CM
Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA.
Clark
April E
AE
Treuting
Piper M
PM
Johnson
Carrie D
CD
Aderem
Alan
A
D051700:Activating Transcription Factor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control / Q000821:virology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C064658:RAG-1 protein; D007371:Interferon-gamma