O'Connor: Non-conventional autophagy and alteration of cholesterol trafficking скачать в хорошем качестве

O'Connor: Non-conventional autophagy and alteration of cholesterol trafficking

Michael O'Connor (University of Minnesota) presents "Non-conventional autophagy in the prothoracic gland mediates a larval nutritional checkpoint through alteration of cholesterol trafficking" at the 59th Annual Drosophila Research Conference, April 11–15, 2018. http://conferences.genetics-gsa.org/d... http://conferences.genetics-gsa.org/d... In Drosophila, the timing of post-embryonic developmental transitions is modulated by various environmental conditions such as nutrient availability. During the L3 stage, starvation causes developmental arrest and /or death if larvae do not first pass through two nutrient-dependent checkpoint known as critical weight (CW) and minimal viable weight (MVW). The molecular mechanism responsible for inducing developmental arrest prior to, but not after, satisfying these checkpoints is not understood. In this study, we demonstrate that starvation strongly induces an autophagy-like process within the PG prior to achieving CW/MVW, but this response is strongly muted as larvae pass through the checkpoint. We show that this autophagy-like process requires many Atg genes and can be suppressed by activation of the insulin/TOR pathway or knockdown of Atg gene expression in the PG leading to precocious pupariation and death. In contrast, if autophagy is hyper-activated in the PG of well-fed larvae after CW/MVW it causes developmental delay. Furthermore, we provide evidence that this autophagy-like process blocks production of the steroid hormone ecdysone by altering the trafficking of cholesterol, its primary precursor. The non-conventional aspect of this process is revealed by an apparent alteration in the fusion of autophagic vesicles with lysosomes. Instead, a dynamic Atg8 positive tubular network is induced in the PG before, but not after, passage through CW/MVW. In addition to confirming non-conventional autophagy as a gatekeeper of metamorphosis, we further find that Anaplastic Lymphoma Kinase (Alk), a receptor tyrosine kinase, works as an autophagy suppressor in late L3 nutrition-restricted (NR) animals. Alk expression in the PG is low during the early L3 stage and then increases as larvae surpass CW/MVW. Expression of constitutively active Alk in the PG prevents NR-induced autophagy in the early L3 stage, while knocking down Alk enables autophagy to be markedly stimulated during late L3 NR animals. In summary, our findings suggest that a nutritionally-regulated non-conventional autophagic-like process, spcifically in the major endocrine organ of larva, is one mechanism by which the CW/MVW checkpoints delay development if sufficient energy reserves have not been sequestered to ensure successful maturation of the juvenile larva into the adult fly. More on genetics at the Genetics Society of America blog: http://genestogenomes.org