The membrane anchored immunophilin zonda is critically required in early stages of starvation-induced autophagy

SORIANELLO E; MELANI M; ROMERO N; VALKO A; ACEVEDO JM; AGUILERA M; DE LA RIVA CARRASCO R; KATZ MJ; PEREZ PERRI J; COLOMBO MI; WAPPNER P

Heidelberg

Conferencia; 24th European Drosophila Research Conference; 2015

DKFZ, University of Heidelberg, EMBL y EMBO

Autophagy is an intracellular process in which damaged organelles and protein aggregates are degraded and recycled for maintaining normal cellular homeostasis. Disruption of autophagic activity promotes cellular stress and death. Moreover, defects in the autophagic machinery have been associated with numerous diseases, including aging-associated pathologies, neurodegeneration, cancer, cardiovascular disorders, and infectious/inflammatory conditions, as well as metabolic problems. Autophagy requires the sequential and concerted activation of many proteins at specific subcellular locations. The first distinguishable autophagy-specific membranous structure, the phagophore, forms when the autophagy-specific VPS34 complex (VPS34, BECN1/ATG6, ATG14 and ATG15) mediates local deposition of phospatidylinositol-3-phospate (PI3P) in a specific membranous domain of the ER that interfaces with mitochondria. The molecules and mechanisms that mediate the assembly and localization of this complex remain however poorly defined. We found that the transmembrane domain-containing immunophilin FKBP38 and its Drosophila orthologue Zonda play a critical role at early stages of starvation-induced autophagy. Zonda operates downstream to ATG1 and is required for autophagy-specific VPS34 activation. Zonda displays a reticular distribution under basal conditions and soon after starvation nucleates in puncta that partially colocalize with ATG8; later in the autophagy process Zonda localizes in autophagosomes and autophagolysosomes. Consistent with a role of FKBP38/Zonda in early stages of autophagy, FKBP38 forms a complex with BECN1 and colocalizes with ATG14 and BECN1. Thus, FKBP38/Zonda is a novel component of the autophagy cascade essential for activation of the VSP34 complex in response to nutrient deprivation.