Michaca, M. H. | bioRxiv Science

bioRxiv2026

ATF4 and EcR interact to mediate both transcriptional activation and repression in the Drosophila fat body

AbstractCells with high secretory and metabolic loads such as adipocytes and hepatocytes rely on constitutive activation of stress response pathways for their homeostatic function and to cope with exogenous stressors such as nutrient deprivation or excess lipids. The evolutionarily conserved stress response factor, Activating Transcription Factor 4 (ATF4), is known to be required for both homeostatic function and exogenous burden in these tissues. However, the molecular mechanism by which ATF4 specifies distinct transcriptional targets under homeostasis versus stress conditions remains an open question. Here, we use the Drosophila larval fat tissue as a model to establish that ATF4 interacts with the steroid hormone receptor Ecdysone Receptor (EcR) to transcriptionally activate and repress genes involved in lipid metabolism. Our data show that EcR and its ligand, 20-hydroxyecdysone, are required for transcription activation of the bona fide ATF4 target 4E-BP in the fat body. We also find that ATF4 and EcR co-repress transcription of the triglyceride lipase brummer (bmm). In Forster resonance energy transfer (FRET) experiments, we find that ATF4 interacts with EcR and does so by competing with the canonical EcR-binding partner, Ultraspiracle (Usp). Using a genetic model of nutrient deprivation, we find that while EcR is required for homeostatic signaling, it is dispensable for the elevated ATF4 signaling associated with nutrient deprivation as measured by induction of 4E-BP. Together, these data provide a mechanistic starting point for understanding how changes in interaction partner allows ATF4 to engage in context-specific transcriptional programs in metabolic tissues.

developmental biology↗

bioRxiv2022

The Hydractinia Allorecognition Complex encodes a novel family of immunoglobulin superfamily proteins

Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2), which encode highly polymorphic cell surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs (ITAMs) and immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility. Significance StatementThe immunoglobulin superfamily (IgSF) is one of the largest and most functionally versatile domain families in animal genomes. Although their amino acid sequences can vary considerably, IgSF domains have been traditionally defined by conserved residues at several key positions in their fold. Here, we sequenced an invertebrate histocompatibility complex and discovered a family of IgSF genes with amino acid sequences that lack most of these residues yet are predicted to adopt folds virtually identical to canonical V-set and I-set IgSF domains. This work broadens the definition of the IgSF and shows that the V-set domain was present earlier in animal evolution than previously appreciated.

genomics↗