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Opposing action of the FLR-2 glycoprotein hormone and DRL-1/FLR-4 MAP kinases balance p38-mediated growth and lipid homeostasis in C. elegans [1]

['Sarah K. Torzone', 'Integrative Program For Biological', 'Genome Sciences', 'The University Of North Carolina At Chapel Hill', 'Chapel Hill', 'North Carolina', 'United States Of America', 'Department Of Biology', 'Aaron Y. Park', 'Peter C. Breen']

Date: 2023-10

Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in the C. elegans intestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations in drl-1 or flr-4 confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of the drl-1 mutant phenotypes and identified mutations in flr-2 and fshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein–coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and protein kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 oligomerization, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development.

While the role of the p38/PMK-1 pathway in regulating innate immunity and oxidative stress responses is well defined [ 21 – 23 ], its function in development, as well as the molecular pathways that converge on p38 signaling to coordinate growth, are poorly understood. Here, we find that mutations in drl-1 or flr-4 severely impair development, growth, and lipid homeostasis in C. elegans, in part by governing the oligomerization and activation of TIR-1/SARM1, a Toll/interleukin-1 receptor (TIR) domain-containing protein that activates p38/PMK-1 signaling [ 24 ]. We show that DRL-1 and FLR-4 are opposed by glycoprotein hormone signaling, which is mediated by the secreted neurohormone FLR-2, its putative intestinal G protein–coupled receptor FSHR-1, and downstream cAMP/protein kinase A (PKA) signaling. Moreover, our data suggest that these opposing pathways may converge on TIR-1 in the intestine to modulate p38 signaling and govern the subcellular localization of the PHA-4/FOXA transcription factor, a well-established regulator of development, to control growth and metabolic homeostasis. Thus, we demonstrate that intestinal p38/PMK-1 activity is coordinated by a non-cell-autonomous hormonal signal and intestinal MAPK pathway to maintain metabolic homeostasis and ensure robust development.

Genetic screens aimed at uncovering genes required for the initiation of vitellogenesis have identified proteins with broader roles in development, metabolism, stress responses, and longevity [ 9 , 14 , 16 ]. Furthermore, impaired vitellogenesis can dramatically alter intestinal lipid levels, and conversely, metabolic dysfunction can down-regulate vitellogenin production, with either event resulting in a defect in overall lipid homeostasis. We previously identified the dietary-restriction-like gene drl-1 in an RNAi screen as a candidate regulator of vitellogenesis [ 14 ]. DRL-1 is a serine–threonine mitogen-activated protein kinase (MAPK) orthologous to mammalian MEKK3 that has been implicated in regulating metabolic, detoxification, and aging pathways [ 17 , 18 ]. Loss of drl-1 increases life span and up-regulates detoxication genes, which requires the p38 MAPK signaling pathway (NSY-1/SEK-1/PMK-1); however, the dietary restriction-like metabolic state triggered by drl-1 knockdown is not entirely dependent on p38 signaling [ 18 ]. Interestingly, loss of a closely related MAP kinase gene, flr-4, induces a similar p38-dependent life span extension and induction of detoxication genes [ 19 , 20 ]. This observation suggests that DRL-1 and FLR-4 may function in the same signaling pathway; however, a biochemical association between these 2 proteins has not been demonstrated.

In many metazoans, including the nematode Caenorhabditis elegans, development into a reproductive adult is marked by production of vitellogenin proteins, which are structural and functional orthologues of the mammalian apoB protein that coordinates very low-density lipoprotein (VLDL) assembly, secretion, and reabsorption in the liver [ 3 ]. In C. elegans, the vitellogenins package intestinal lipids into VLDL-like particles, which are then secreted and captured by the LDL receptor RME-2 in oocytes [ 4 , 5 ]. The vitellogenin-associated lipids promote the recruitment of sperm to the oocyte during fertilization [ 6 ], support robust development of the progeny [ 7 ], and facilitate larval survival during starvation conditions [ 8 , 9 ]. While crucial for reproduction and the developmental success of the progeny, reallocation of these key lipid resources restricts maternal longevity [ 10 , 11 ]. Consistently, this metabolic trade-off can be finely tuned and is highly regulated by developmental, nutritional, and metabolic regulatory pathways [ 10 , 12 – 16 ]. The molecular basis of how these developmental regulators impact metabolic decisions to maintain organismal homeostasis is poorly understood.

Animals respond to environmental, nutritional, and developmental cues to balance resources between essential biological processes, ensuring fitness and reproductive fidelity. In metazoans, reproduction is a metabolically expensive process, requiring organisms to shift somatic energy stores to the germline to support the development of their offspring. This metabolic trade-off ensures reproductive fitness while restricting the somatic maintenance programs that support longevity [ 1 , 2 ]. The energetic balance between somatic and germline functions is coordinated by complex regulatory networks across diverse tissues that integrate developmental and environmental inputs; however, the homeostatic mechanisms that govern these metabolic trade-offs are not fully understood.

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002320

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