A Tissue- and Temporal-Specific Autophagic Switch Controls Drosophila Pre-metamorphic Nutritional Checkpoints.

Properly timed production of steroid hormones by endocrine tissues regulates juvenile-to-adult transitions in both mammals (puberty) and holometabolous insects (metamorphosis). Nutritional conditions influence the temporal control of the transition, but the mechanisms responsible are ill defined. Here we demonstrate that autophagy acts as an endocrine organ-specific, nutritionally regulated gating mechanism to help ensure productive metamorphosis in Drosophila. Autophagy in the endocrine organ is specifically stimulated by nutrient restriction at the early, but not the late, third-instar larva stage. The timing of autophagy induction correlates with the nutritional checkpoints, which inhibit precocious metamorphosis during nutrient restriction in undersized larvae. Suppression of autophagy causes dysregulated pupariation of starved larvae, which leads to pupal lethality, whereas forced autophagy induction results in developmental delay/arrest in well-fed animals. Induction of autophagy disrupts production of the steroid hormone ecdysone at the time of pupariation not by destruction of hormone biosynthetic capacity but rather by limiting the availability of the steroid hormone precursor cholesterol in the endocrine cells via a lipophagy mechanism. Interestingly, autophagy in the endocrine organ functions by interacting with the endolysosome system, yet shows multiple features not fully consistent with a canonical autophagy process. Taken together, our findings demonstrate an autophagy mechanism in endocrine cells that helps shape the nutritional checkpoints and guarantee a successful juvenile-to-adult transition in animals confronting nutritional stress.

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