NPR2/3 define a novel nutrient stress pathway in the Drosophila ovary. Youheng Wei, John Reich, Weili Cai, Tanveer Akbar, Kuikwon Kim, Mary Lilly. Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

   Drosophila oogenesis is highly sensitive to nutritional inputs. Under protein poor conditions, mid-stage (stage 8/9) egg chambers degenerate. In contrast, young egg chambers (stage 2 to 7) remain intact so that egg production can resume when nutrient availability improves. The pathways that protect young egg chambers under nutrient stress are poorly defined. During starvation the activity of the nutrient sensitive kinase, Target of Rapamycin (TOR) is down regulated. The inhibition of TOR activity triggers autophagy, a catabolic process that provides nutrients for cell survival during starvation through a lysosomal-mediated process of cytoplasmic degradation. In yeast the NPR2 and NPR3 proteins physically interact and mediate a response to amino acid starvation upstream of the TOR pathway and have been implicated in the regulation of autophagy. Intriguingly, in yeast NPR2 and NPR3 regulate early meiotic progression and sporulation (gametogenesis). We have determined that the basic metabolic functions of NPR2 and NPR3 have been conserved in metazoans. We found that, as is observed in yeast, in Drosophila NPR2 physically interacts with NPR3. Additionally, upon starvation the NPR2 and NPR3 proteins target to autophagosomes. Moreover, our data indicate that knocking down NPR2 or NPR3 in the female germ line results in ovaries being acutely sensitive to nutrient limitation. Specifically, in the absence of NPR2 and NPR3 young egg chambers die at high rates under starvation conditions. Our data suggest that this starvation sensitivity is due to the inability to down regulate TOR activity in response to nutrient stress. Finally, we defined a unique role for NPR2 and NPR3 in the regulation of early oogenesis. In summary, our data indicate that the evolutionarily conserved NPR2/3 complex regulates the response to starvation and gametogenesis in the Drosophila ovary.