控制代谢对繁殖的分子机制,这通常是以牺牲体细胞储备为代价的,仍然知之甚少。我们确定秀丽隐杆线虫F-box蛋白FBXL-5是母体提供卵黄蛋白原脂蛋白的负调节因子,介导肠道脂质向种系的转移。fbxl-5的突变部分抑制了异慢性突变体lin-4和lin-29中观察到的卵黄形成缺陷,这两种突变体在成年发育阶段都异位表达fbxl-5。FBXL-5在肠道中起着负向调节卵黄蛋白原基因表达的作用;并且始终如一地,FBXL-5的肠特异性过表达足以抑制卵黄发生,限制脂质积累,并缩短寿命。我们的上位性分析表明,fbxl-5的功能与cullin基因cul-6一致,和Skp1相关基因skr-3调节卵黄发生。此外,fbxl-5在rict-1的基因上游起作用,rict-1编码核心mTORC2蛋白Rictor,控制卵黄发生。一起,我们的结果揭示了SCF泛素-连接酶复合物通过参与mTORC2信号传导在控制肠道脂质稳态中的意想不到的作用。
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 Caenorhabditis elegans 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 fbxl-5 partially suppress the
vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 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 fbxl-5 functions in concert with cul-6, a cullin gene, and the Skp1-related gene skr-3 to regulate
vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1, 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.