PgmNr D200: Endosomal Microautophagy: a genetic model in Drosophila.

Authors:
A. Mukherjee; B. Patel; H. Koga; A. M. Cuervo; A. Jenny


Institutes
Albert Einstein College of Medicine, Bronx, NY.


Keyword: metabolism

Abstract:

Autophagy is an essential pathway that maintains the energy balance of cells by lysosomal degradation and recycling of dysfunctional proteins and organellar components. Importantly, autophagy also provides nutrients including amino acids and lipids to cells under stress conditions and is thus essential for energy balance.  As such, autophagy counteracts various human diseases (related to liver, kidney and the nervous system), and its reduction leads to aging like phenotypes. Macroautophagy (MA), the best studied form of autophagy to this date, selectively degrades organelles or aggregated proteins, but selective degradation of single proteins has only been described for Chaperone-mediated autophagy (CMA) and endosomal Microautophagy (eMI). These two autophagic pathways, described to date only in mammals, are specific for cytosolic proteins containing KFERQ-related targeting motifs. However, CMA and eMI have only been described in mammals and thus lack a model in a genetically easily tractable organism.

  Using transgenic flies expressing a KFERQ-tagged fluorescent biosensor, we have identified and functionally characterized an eMI-like pathway in Drosophila melanogaster. Our functional in vivo studies in fly fat body (functionally equivalent to the mammalian liver) reveal that the biosensor forms puncta in response to prolonged starvation and co-localizes with lysosomes/late endosomes in a KFERQ- and Hsc70- dependent manner. Furthermore, fly eMI requires endosomal multivesicular body formation mediated by ESCRT complex components. Importantly, induction of Drosophila eMI requires longer starvation than the induction of MA and is independent of the critical MA genes atg5, atg7, and atg12.

  Tor signaling represses MA by inactivating the Atg1/Atg13 complex. Interestingly, inhibition of Tor signaling is also sufficient to induce eMI in flies under nutrient rich conditions, and, as eMI in Drosophila also requires atg1 and atg13, our data suggest that these genes may have a novel, additional role in regulating eMI in flies.

  Overall, our data provide the evidence for a novel, starvation inducible catabolic process resembling endosomal Microautophagy in a non-mammalian species in vivo. It is tempting to speculate that Drosophila eMI is an older form of selective autophagy that fulfills functions that in mammals are shared between eMI (likely the constitutive form) and CMA (the starvation-induced variant).