Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Dev Cell. 2019 Mar 11;48(5):659-671.e4. doi: 10.1016/j.devcel.2019.01.007. Epub 2019 Feb 21.
Steroid hormones are important signaling molecules that regulate growth and drive the development of many cancers. These factors act as long-range signals that systemically regulate the growth of the entire organism, whereas the Hippo/Warts tumor-suppressor pathway acts locally to limit organ growth. We show here that autophagy, a pathway that mediates the degradation of cellular components, also controls steroid production. This process is regulated by Warts (in mammals, LATS1/2) signaling, via its effector microRNA bantam, in response to nutrients. Specifically, autophagy-mediated mobilization and trafficking of the steroid precursor cholesterol from intracellular stores controls the production of the Drosophila steroid ecdysone. Furthermore, we also show that bantam regulates this process via the ecdysone receptor and Tor signaling, identifying pathways through which bantam regulates autophagy and growth. The Warts pathway thus promotes nutrient-dependent systemic growth during development by autophagy-dependent steroid hormone regulation (ASHR). These findings uncover an autophagic trafficking mechanism that regulates steroid production.
甾体激素是重要的信号分子，可调节生长并促进许多癌症的发展。这些因子作为长距离信号，系统性地调节整个生物体的生长，而 Hippo/Warts 肿瘤抑制途径则在局部限制器官生长。我们在此表明，自噬是一种介导细胞成分降解的途径，也控制着甾体激素的产生。该过程受 Warts（在哺乳动物中为 LATS1/2）信号通过其效应 microRNA bantam 调控，以响应营养物质。具体而言，自噬介导的甾体激素前体胆固醇从细胞内储存中的动员和运输控制着果蝇甾体激素蜕皮激素的产生。此外，我们还表明 bantam 通过蜕皮激素受体和 Tor 信号通路调节该过程，确定了 bantam 调节自噬和生长的途径。因此，Warts 途径通过自噬依赖性甾体激素调节（ASHR）促进发育过程中营养物质依赖性全身生长。这些发现揭示了一种调节甾体激素产生的自噬运输机制。
