Autophagy-Mediated Cholesterol Trafficking Controls Steroid Production

• Published in: Developmental cell Vol. 48; no. 5; pp. 659 - 671.e4
• Main Authors: Texada, Michael J., Malita, Alina, Christensen, Christian F., Dall, Kathrine B., Faergeman, Nils J., Nagy, Stanislav, Halberg, Kenneth A., Rewitz, Kim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2019
• Subjects: autophagy; bantam; cholesterol; Drosophila; ecdysone; EcR; prothoracic gland; steroid; steroidogenesis; Tor; warts; autophagy; bantam; ecdysone; EcR; Drosophila; Tor; steroidogenesis; cholesterol; prothoracic gland; warts; steroid
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.01.007

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. [Display omitted] •Autophagy regulates steroid production•Autophagosomes sequester and traffic cholesterol substrate for steroid production•The Warts effector microRNA bantam regulates autophagy via the EcR and Tor pathways•Autophagy-dependent steroid regulation adjusts growth to nutrient availability Steroid hormones are produced from cholesterol and control growth and development. Texada et al. describe an autophagosomal mechanism, regulated by the Warts/LATS1/2 tumor-suppressor pathway, that controls steroid production through mobilization of stored precursor cholesterol.