Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

Abstract

A nimal growth and development rely on coordinated functions of body organs to balance energy consumption and storage under optimal or challenging conditions, such as food scarcity or pathogen attack. When adverse conditions are temporary, animals survive by lengthening development and postponing maturity, reducing their body size (16,65). In contrast, prolonged starvation or chronic inflammation may exhaust energy reserves, causing death (32, 69). The key nutrient-sensing, metabolic, and immune-signaling pathways are functionally conserved across phyla. In the fruit fly Drosophila melanogaster, as in vertebrates, insulin/insulin growth factor (IGF) signaling (IIS) primarily regulates growth and metabolic homeostasis (56). The innate immune response of the fly relies on the Toll receptor and the immune deficiency (Imd) pathways (35). In response to bacterial or fungal infection, the Toll and Imd pathways engage downstream transcription factors of the NF-B-like family (Dif, Dorsal, and Relish) that in turn trigger synthesis of a battery of antimicrobial peptides (AMPs).It has become evident that the metabolic and immune system responses are tightly interconnected. Selective activation of Toll signaling in the Drosophila fat body attenuates IIS to reduce nutrient stores and overall growth (14). Mycobacterial infection causes energy wasting due to the systemic activation of the Forkhead transcription factor FOXO (15). Activation of the Jun N-terminal kinase (JNK) pathway is a well-established example of antagonistic regulation of IIS in both flies and vertebrates (29). Chronic inflammation, accompanied by high JNK activity, is at the heart of the metabolic syndrome and type 2 diabetes (54). Interestingly, genetic removal of IIS pathway components, starvation, and DNA damage all induce AMP expression in the absence of infection. This infection-independent AMP upregulation requires both FOXO (5) and Relish (30,70), further supporting the notion that maintenance of metabolic and innate immune balance are intimately linked.The Drosophila fat body and gut integrate metabolic and inflammatory signals to coordinate energy use. The fly alimentary tract digests and absorbs nutrients, while the fat body metabolizes and stores them. In addition, both organs can mount an immune response. The fat body requires both the Toll and Imd pathways for AMP production, whereas the gut immune response relies solely on Imd signaling (35,62). In contrast to the low basal immune activity within the unchallenged fat body, the presence of commensal bacteria in the gut lumen keeps the gut epithelium permanently alert with activated nuclear Relish. In this case, additional factors, such as the homeobox gene caudal (49), control AMP expression. Tightly regulated production of positive and negative Imd modulators prevents overgrowth of pathogens while preserving beneficial commensal bacteria. Uncontrolled inflammatory response of the intestinal epithelium has a dramatic impact on gut physiology and homeostasis in both flies and humans (43,47). A ...

Immune-metabolic interaction in Drosophila

“…Similarly, the transcription factor ATF3 inhibits antimicrobial peptide expression and metabolic storage in larvae; it is difficult to directly compare the function of Atf3 with that of Mef2 because of the many differences in experimental approach, but the function of Atf3 appears broadly opposite to that we ascribe to Mef2. 36 In this regard, it may be relevant that our computational analysis identified an association between CREB/ ATF sites and antimicrobial peptides.…”

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

“…Based on our finding of a potential activation in stress signaling in fly models of SMA, an important question moving forward will be to understand how loss of SMN causes this stress response. By text mining with the stress signatures identified in the SMA models described here, we found that mutations in the Activating transcription factor 3 (Atf3) gene cause a similar dysregulation in immune and metabolic homeostasis (Rynes et al 2012). Among other things, this signaling pathway appears to regulate the cytosolic formation of SMN-containing U-bodies in human cells in response to bacterial pathogens (Tsalikis et al 2015).…”

Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression

“…In silico analysis of the DNM3os promoter showed seven putative cis-binding sites for ATF3; of these, the two sites nearest the transcription start site of DNM3os were required for PlGF-mediated repression. ATF3, as a member of the ATF/CREB family of basic leucine zipper transcription factors, is induced by an array of signals originating from cytokines, physiological changes, and pathological stimuli (20,(39)(40)(41)(42)(43)(44)(45). ATF3 protein can form heterodimers with AP-1 complex, JDP2, and ATF2 (19,41,42,44,46).…”