THE MEMBRANE-BOUND IMMUNOPHILINZONDA IS ESSENTIALIN EARLY STAGES OF STARVATION-INDUCED AUTOPHAGY IN DROSOPHILA

SORIANELLO E; WAPPNER P; VALKO A; MELANI M

La Serena

Workshop; Actualizations in membrane trafficking in health and disease; 2016

EMBO

Degradation of cellular material by autophagy is essential for cell survival and homeostasis.Autophagy is an intracellular process in which damaged organelles and protein aggregates are degraded and recycled for maintaining normal cellular function.Defects in autophagic activity lead to cellular stress and death. Furthermore, impaired autophagic machinery has been linked to many diseases, including neurodegeneration, cancer, cardiovascular disorders, aging-associated pathologies as well as metabolic alterations. The autophagic process requires sequentially activation of many proteins at specific subcellular locations. Upon amino acid starvation the initiation complex(ATG1, ATG13, ATG17 and ATG101) forms. Once phosphorylated by ATG1 the active autophagy-specific VPS34 complex (VPS34, BECN1/ATG6, ATG14 and ATG15) triggers the deposition of phosphatidylinositol-3-phosphate (PI3P) at specific ER domains initiating the formation of omegasomes from where thephagophore, which isthe first detectable autophagic membranous structure, will sprout.The molecules and mechanisms that mediate the assembly and localization of the VPS34complex remain poorly defined.We found that the membrane-bound immunophylinZonda is required at early steps of the autophagy process in Drosophila. While in fed conditions Zondahas a reticular distribution and localizes to the ER, under nutrient deprivationZondanucleates and colocalizes with early autophagy markersin the fat body of third instar larvae.Zonda nucleation is dependent on ATG1, ATG17 and VPS34. Furthermore, Zonda is required for VPS34 activity during autophagy, as it is essential for PI3P deposition on the omegasome at the beginning of the autophagy cascade.In addition, transmission electron microscopy (TEM) analysis revealed that Zonda is necessary for the formation of autophagy-like structures during starvation. In conclusion, we discovered and characterize a new component of the autophagy cascade named Zonda, which is required at early steps of the autophagy process.