Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2012 Aug 2

PMID 22851689

Citations 47

Authors

Jan Rynes

Colin D Donohoe

Peter Frommolt

Susanne Brodesser

Marek Jindra

Mirka Uhlirova

Affiliations

Soon will be listed here.

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-κB/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.

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References

Dionne M, Pham L, Shirasu-Hiza M, Schneider D . Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr Biol. 2006; 16(20):1977-85. DOI: 10.1016/j.cub.2006.08.052. View

Davis M, Primrose D, Hodgetts R . A member of the p38 mitogen-activated protein kinase family is responsible for transcriptional induction of Dopa decarboxylase in the epidermis of Drosophila melanogaster during the innate immune response. Mol Cell Biol. 2008; 28(15):4883-95. PMC: 2493365. DOI: 10.1128/MCB.02074-07. View

Jiang H, Wek S, McGrath B, Lu D, Hai T, Harding H . Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol. 2004; 24(3):1365-77. PMC: 321431. DOI: 10.1128/MCB.24.3.1365-1377.2004. View

Gronke S, Mildner A, Fellert S, Tennagels N, Petry S, Muller G . Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab. 2005; 1(5):323-30. DOI: 10.1016/j.cmet.2005.04.003. View

Hartman M, Kociba G, Hai T . The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression. J Biol Chem. 2002; 277(22):20020-5. DOI: 10.1074/jbc.M200727200. View

Hull-Thompson J, Muffat J, Sanchez D, Walker D, Benzer S, Ganfornina M . Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 2009; 5(4):e1000460. PMC: 2667264. DOI: 10.1371/journal.pgen.1000460. View

Hedengren M, Asling B, Dushay M, Ando I, Ekengren S, Wihlborg M . Relish, a central factor in the control of humoral but not cellular immunity in Drosophila. Mol Cell. 2000; 4(5):827-37. DOI: 10.1016/s1097-2765(00)80392-5. View

Slack C, Giannakou M, Foley A, Goss M, Partridge L . dFOXO-independent effects of reduced insulin-like signaling in Drosophila. Aging Cell. 2011; 10(5):735-48. PMC: 3193374. DOI: 10.1111/j.1474-9726.2011.00707.x. View

Zuberova M, Fenckova M, Simek P, Janeckova L, Dolezal T . Increased extracellular adenosine in Drosophila that are deficient in adenosine deaminase activates a release of energy stores leading to wasting and death. Dis Model Mech. 2010; 3(11-12):773-84. DOI: 10.1242/dmm.005389. View

10.

DiAngelo J, Bland M, Bambina S, Cherry S, Birnbaum M . The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling. Proc Natl Acad Sci U S A. 2009; 106(49):20853-8. PMC: 2791644. DOI: 10.1073/pnas.0906749106. View

11.

Rutschmann S, Jung A, Zhou R, Silverman N, Hoffmann J, Ferrandon D . Role of Drosophila IKK gamma in a toll-independent antibacterial immune response. Nat Immunol. 2001; 1(4):342-7. DOI: 10.1038/79801. View

12.

Cai D, Yuan M, Frantz D, Melendez P, Hansen L, Lee J . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11(2):183-90. PMC: 1440292. DOI: 10.1038/nm1166. View

13.

Lyne R, Smith R, Rutherford K, Wakeling M, Varley A, Guillier F . FlyMine: an integrated database for Drosophila and Anopheles genomics. Genome Biol. 2007; 8(7):R129. PMC: 2323218. DOI: 10.1186/gb-2007-8-7-r129. View

14.

HARTMAN M, Kociba G, Hai T . The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas. J Biol Chem. 2001; 276(31):29507-14. DOI: 10.1074/jbc.M100986200. View

15.

Muniz C, Jaillard D, Lemaitre B, Boccard F . Erwinia carotovora Evf antagonizes the elimination of bacteria in the gut of Drosophila larvae. Cell Microbiol. 2006; 9(1):106-19. DOI: 10.1111/j.1462-5822.2006.00771.x. View

16.

Gilchrist M, Thorsson V, Li B, Rust A, Korb M, Roach J . Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature. 2006; 441(7090):173-8. DOI: 10.1038/nature04768. View

17.

Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky A, Martinez-Arias A . puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Genes Dev. 1998; 12(4):557-70. PMC: 316530. DOI: 10.1101/gad.12.4.557. View

18.

De Gregorio E, Spellman P, Tzou P, Rubin G, Lemaitre B . The Toll and Imd pathways are the major regulators of the immune response in Drosophila. EMBO J. 2002; 21(11):2568-79. PMC: 126042. DOI: 10.1093/emboj/21.11.2568. View

19.

Lemaitre B, Hoffmann J . The host defense of Drosophila melanogaster. Annu Rev Immunol. 2007; 25:697-743. DOI: 10.1146/annurev.immunol.25.022106.141615. View

20.

Nakade K, Pan J, Yoshiki A, Ugai H, Kimura M, Liu B . JDP2 suppresses adipocyte differentiation by regulating histone acetylation. Cell Death Differ. 2007; 14(8):1398-405. DOI: 10.1038/sj.cdd.4402129. View