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Mol. Cell. Biol. 32 (19): 3949-3962

Copyright © 2012 by the American Society for Microbiology. All rights reserved.

Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

Jan Rynes,a,b Colin D. Donohoe,a Peter Frommolt,c Susanne Brodesser,d Marek Jindra,e, and Mirka Uhlirovaa

Institute for Genetics and Cologne Excellence Cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany,a Department of Molecular Biology, University of South Bohemia, Ceske Budejovice, Czech Republic,b Bioinformatics Core Facility, CECAD, and Cologne Center for Genomics, Cologne, Germany,c Lipidomics Core Facility, CECAD, and Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany,d Biology Center, Academy of Sciences of the Czech Republic, Ceske Budejovice, Czech Republic,e

Received for publication 30 March 2012. Revision received 21 April 2012. Accepted for publication 18 July 2012.

Abstract: Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-{kappa}B/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins.

Address correspondence to Mirka Uhlirova, mirka.uhlirova{at}

J.R. and C.D.D. contributed equally to this work.

Published ahead of print 30 July 2012

Supplemental material for this article may be found at

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