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Rapidly renewable tissues adapt different strategies to cope with environmental insults. While tissue repair is associated with increased intestinal stem cell (ISC) proliferation and accelerated tissue turnover rates, reduced calorie intake triggers a homeostasis-breaking process causing adaptive resizing of the gut. Here we show that activins are key drivers of both adaptive and regenerative growth. Activin-β (Actβ) is produced by stem and progenitor cells in response to intestinal infections and stimulates ISC proliferation and turnover rates to promote tissue repair. Dawdle (Daw), a divergent Drosophila activin, signals through its receptor, Baboon, in progenitor cells to promote their maturation into enterocytes (ECs). Daw is dynamically regulated during starvation-refeeding cycles, where it couples nutrient intake with progenitor maturation and adaptive resizing of the gut. Our results highlight an activin-dependent mechanism coupling nutrient intake with progenitor-to-EC maturation to promote adaptive resizing of the gut and further establish activins as key regulators of adult tissue plasticity., (© 2024. The Author(s).)

It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.

Background: Adherens junctions (AJs) provide structure to epithelial tissues by connecting adjacent cells through homophilic E-cadherin interactions and are linked to the actin cytoskeleton via the intermediate binding proteins beta-catenin and alpha-catenin. Rather than being static structures, AJs are extensively remodeled during development, allowing the cell rearrangements required for morphogenesis. Several "noncore" AJ components have been identified, which modulate AJs to promote this plasticity but are not absolutely required for cell-cell adhesion., Results: We previously identified dASPP as a positive regulator of dCsk (Drosophila C-terminal Src kinase). Here we show that dRASSF8, the Drosophila RASSF8 homolog, binds to dASPP and that this interaction is required for normal dASPP levels. Our genetic and biochemical data suggest that dRASSF8 acts in concert with dASPP to promote dCsk activity. Both proteins specifically localize to AJs and are mutually required for each other's localization. Furthermore, we observed abnormal E-cadherin localization in mutant pupal retinas, correlating with aberrant cellular arrangements. Loss of dCsk or overexpression of Src elicited similar AJ defects., Conclusions: Because Src is known to regulate AJs in both Drosophila and mammals, we propose that dASPP and dRASSF8 fine tune cell-cell adhesion during development by directing dCsk and Src activity. We show that the dASPP-dRASSF8 interaction is conserved in humans, suggesting that mammalian ASPP1/2 and RASSF8, which are candidate tumor-suppressor genes, restrict the activity of the Src proto-oncogene.

Eukaryotic initiation factor 4E (eIF4E) controls a crucial step of translation initiation and is critical for cell growth . Biochemical studies have shown that it undergoes a regulated phosphorylation by the MAP-kinase signal-integrating kinases Mnk1 and Mnk2 . Although the role of eIF4E phosphorylation in mammalian cells has remained elusive , recent work in Drosophila has established that it is required for growth and development . Here, we demonstrate that a previously identified Drosophila kinase called Lk6 is the functional homolog of mammalian Mnk kinases. We generated lk6 loss-of-function alleles and found that eIF4E phosphorylation is dramatically reduced in lk6 mutants. Importantly, lk6 mutants exhibit reduced viability, slower development, and reduced adult size, demonstrating that Lk6 function is required for organismal growth. Moreover, we show that uniform lk6 expression rescues the lethality of eIF4E hypomorphic mutants in an eIF4E phosphorylation site-dependent manner and that the two proteins participate in a common complex in Drosophila S2 cells, confirming the functional link between Lk6 and eIF4E. This work demonstrates that Lk6 exerts a tight control on eIF4E phosphorylation and is necessary for normal growth and development.

Drosophila tumor suppressor genes have revealed molecular pathways that control tissue growth, but mechanisms that regulate mitogenic signaling are far from understood. Here we report that the Drosophila TSG tumorous imaginal discs (tid), whose phenotypes were previously attributed to mutations in a DnaJ-like chaperone, are in fact driven by the loss of the N-linked glycosylation pathway component ALG3. tid/alg3 imaginal discs display tissue growth and architecture defects that share characteristics of both neoplastic and hyperplastic mutants. Tumorous growth is driven by inhibited Hippo signaling, induced by excess Jun N-terminal kinase (JNK) activity. We show that ectopic JNK activation is caused by aberrant glycosylation of a single protein, the fly tumor necrosis factor (TNF) receptor homolog, which results in increased binding to the continually circulating TNF. Our results suggest that N-linked glycosylation sets the threshold of TNF receptor signaling by modifying ligand-receptor interactions and that cells may alter this modification to respond appropriately to physiological cues.

While the role of the Tumor necrosis factor-α (referred to as TNF here) as a key mediator of pro-inflammatory and immune responses is well-established, non-pathological functions of the TNF-TNF receptor (TNFR) signaling are less explored. In this issue of The EMBO Journal, Esteban-Collado et al, (2024) describe a TNF independent, pro-survival role of the Drosophila TNFR Wengen during damage-induced tissue regeneration. Recent study identifies the Drosophila TNF receptor Wengen as a TNF-independent mediator of tissue regeneration in response to apoptosis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)‐α is a highly conserved proinflammatory cytokine with important functions in immunity, tissue repair, and cellular homeostasis. Due to the simplicity of the Drosophila TNF‐TNF receptor (TNFR) system and a broad genetic toolbox, the fly has played a pivotal role in deciphering the mechanisms underlying TNF‐mediated physiological and pathological functions. In this review, we summarize the recent advances in our understanding of how local and systemic sources of Egr/TNF contribute to its antitumor and tumor‐promoting properties, and its emerging functions in adaptive growth responses, sleep regulation, and adult tissue homeostasis. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity‐ and cancer‐associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis. Here, we discuss the role of TNFR signaling in coupling immune and metabolic processes and how this might be relevant in the adaption of host to environmental stresses, or, in the case of obesity, promote metabolic derangements and disease. [ABSTRACT FROM AUTHOR]

The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions. The Drosophila tumour necrosis factor (TNF) system comprises a single ligand Eiger (Egr) and two receptors. The structure of Egr in complex with the extracellular domain of the receptor Grindelwald and accompanying data suggest that distinct affinities of TNF ligand for its receptors mediate non-redundant functions. [ABSTRACT FROM AUTHOR]

Summary Early transplantation and grafting experiments suggest that body organs follow autonomous growth programs [ 1–3 ], therefore pointing to a need for coordination mechanisms to produce fit individuals with proper proportions. We recently identified Drosophila insulin-like peptide 8 (Dilp8) as a relaxin and insulin-like molecule secreted from growing tissues that plays a central role in coordinating growth between organs and coupling organ growth with animal maturation [ 4, 5 ]. Deciphering the function of Dilp8 in growth coordination relies on the identification of the receptor and tissues relaying Dilp8 signaling. We show here that the orphan receptor leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), a member of the highly conserved family of relaxin family peptide receptors (RXFPs), mediates the checkpoint function of Dilp8 for entry into maturation. We functionally identify two Lgr3-positive neurons in each brain lobe that are required to induce a developmental delay upon overexpression of Dilp8. These neurons are located in the pars intercerebralis, an important neuroendocrine area in the brain, and make physical contacts with the PTTH neurons that ultimately control the production and release of the molting steroid ecdysone. Reducing Lgr3 levels in these neurons results in adult flies exhibiting increased fluctuating bilateral asymmetry, therefore recapitulating the phenotype of dilp8 mutants. Our work reveals a novel Dilp8/Lgr3 neuronal circuitry involved in a feedback mechanism that ensures coordination between organ growth and developmental transitions and prevents developmental variability. [ABSTRACT FROM AUTHOR]

Summary: Src-family kinases (SFKs) control a variety of biological processes, from cell proliferation and differentiation to cytoskeletal rearrangements. Abnormal activation of SFKs has been implicated in a wide variety of cancers and is associated with metastatic behavior (). SFKs are maintained in an inactive state by inhibitory phosphorylation of their C-terminal region by C-terminal Src kinase (Csk). We have identified Drosophila Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein (dASPP) as a regulator of Drosophila Csk (dCsk) activity. dASPP is the homolog of the mammalian ASPP proteins, which are known to bind to and stimulate the proapoptotic function of p53. We show that dASPP is a positive regulator of dCsk. First, dASPP loss-of-function strongly enhances the specific phenotypes of dCsk mutants in wing epithelial cells. Second, dASPP interacts physically with dCsk to potentiate the inhibitory phosphorylation of Drosophila Src (dSrc). Our results suggest a role for dASPP in maintaining epithelial integrity through dCsk regulation. [Copyright &y& Elsevier]

Insulin signaling is a conserved feature in all metazoans. It evolved with the appearance of multicellularity, allowing primordial metazoans to respond to a greater diversity of environmental signals. The insulin signaling pathway is highly conserved in insects and particularly in Drosophila, where it has been extensively studied in recent years and shown to control metabolism, growth, reproduction, and longevity. Because misregulation of the insulin/IGF pathway in humans plays a role in many medical disorders, such as diabetes and various types of cancer, unraveling the regulation of insulin/IGF signaling using the power of a genetically tractable organism like Drosophila may contribute to the amelioration of these major human pathologies. [ABSTRACT FROM AUTHOR]

All animals coordinate growth and maturation to reach their final size and shape. In insects, insulin family molecules control growth and metabolism, whereas pulses of the steroid 20-hydroxyecdysone (20E) initiate major developmental transitions. We show that 20E signaling also negatively controls animal growth rates by impeding general insulin signaling involving localization of the transcription factor dFOXO and transcription of the translation inhibitor 4E-BP. We also demonstrate that the larval fat body, equivalent to the vertebrate liver, is a key relay element for ecdysone-dependent growth inhibition. Hence, ecdysone counteracts the growth-promoting action of insulins, thus forming a humoral regulatory loop that determines organismal size. [ABSTRACT FROM AUTHOR]

Organisms modulate their growth according to nutrient availability. Although individual cells in a multicellular animal may respond directly to nutrient levels, growth of the entire organism needs to be coordinated. Here, we provide evidence that in Drosophila, coordination of organismal growth originates from the fat body, an insect organ that retains endocrine and storage functions of the vertebrate liver. In a genetic screen for growth modifiers, we identified slimfast, a gene that encodes an amino acid transporter. Remarkably, downregulation of slimfast specifically within the fat body causes a global growth defect similar to that seen in Drosophila raised under poor nutritional conditions. This involves TSC/TOR signaling in the fat body, and a remote inhibition of organismal growth via local repression of PI3-kinase signaling in peripheral tissues. Our results demonstrate that the fat body functions as a nutrient sensor that restricts global growth through a humoral mechanism. [Copyright &y& Elsevier]

Drosophila MCRS2 (dMCRS2; MCRS2/MSP58 and its splice variant MCRS1/p78 in humans) belongs to a family of forkhead-associated (FHA) domain proteins. Whereas human MCRS2 proteins have been associated with a variety of cellular processes, including RNA polymerase I transcription and cell cycle progression, dMCRS2 has been largely uncharacterized. Recent data show that MCRS2 is purified as part of a complex containing the histone acetyltransferase MOF (males absent on first) in both humans and flies. MOF mediates H4K16 acetylation and regulates the expression of a large number of genes, suggesting that MCRS2 could also have a function in transcription regulation. Here, we show that dMCRS2 copurifies with RNA polymerase II (RNAP II) complexes and localizes to the 5' ends of genes. Moreover, dMCRS2 is required for optimal recruitment of RNAP II to the promoter regions of cyclin genes. In agreement with this, dMCRS2 is required for normal levels of cyclin gene expression. We propose a model whereby dMCRS2 promotes gene transcription by facilitating the recruitment of RNAP II preinitiation complexes (PICs) to the promoter regions of target genes. [ABSTRACT FROM AUTHOR]

How organs scale with other body parts is not mechanistically understood. We have addressed this question using the Drosophila imaginal disc model. When the growth of one disc domain is perturbed, other parts of the disc and other discs slow down their growth, maintaining proper inter-disc and intra-disc proportions. We show here that the relaxin-like Dilp8 is required for this inter-organ coordination. Our work also reveals that the stress-response transcription factor Xrp1 plays a key role upstream of dilp8 in linking organ growth status with the systemic growth response. In addition, we show that the small ribosomal subunit protein RpS12 is required to trigger Xrp1-dependent non-autonomous response. Our work demonstrates that RpS12, Xrp1, and Dilp8 form an independent regulatory module that ensures intra- and inter-organ growth coordination during development. • Dilp8 triggers inter-organ coordination and remote growth inhibition • The stress-response factor Xrp1 activates Dilp8 upon local growth impairment • Xrp1 overexpression is sufficient to trigger IOC in a Dilp8-dependent manner • RpS12 is required for IOC upstream of Dilp8, acting as a sensor of tissue growth All organs adjust their growth trajectory to a local growth perturbation, ensuring proper body proportion. Boulan et al. use the fly model to unravel this inter-organ coordination: growth-impaired organs activate the Xrp1 stress-response pathway, leading to the production of the Dilp8 hormone and the systemic growth inhibition of undamaged organs. [ABSTRACT FROM AUTHOR]