AUTHOR=Breen Peter C. , Kanakanui Kendall G. , Newman Martin A. , Dowen Robert H. 

TITLE=The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1389077

DOI=10.3389/fcell.2024.1389077

ISSN=2296-634X

ABSTRACT=<p>The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the <italic>Caenorhabditis elegans</italic> F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in <italic>fbxl-5</italic> partially suppress the vitellogenesis defects observed in the heterochronic mutants <italic>lin-4</italic> and <italic>lin-29,</italic> both of which ectopically express <italic>fbxl-5</italic> at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that <italic>fbxl-5</italic> functions in concert with <italic>cul-6</italic>, a cullin gene, and the Skp1-related gene <italic>skr-3</italic> to regulate vitellogenesis. Additionally, <italic>fbxl-5</italic> acts genetically upstream of <italic>rict-1</italic>, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.</p>