Autophagy is a conserved catabolic process that plays a pivotal role in homeostasis, and whose relevance has been demonstrated by the diseases originating from its dysfunction. It can be both a non-selective bulk degradation process to provide nutrients to cells, and a selective mechanism to remove toxic material from the cells. Until recently, selective autophagy was thought to exclusively rely on the binding of autophagy receptors to LC3 moieties for the transfer of the cargoes to the growing phagophore. New studies have demonstrated existence of an alternative pathway in which the autophagy receptors directly engage the upstream autophagy protein FIP200 to form an in situ phagophore around the cargo, thereby bypassing the need for LC3. The study of this new pathway has however been hampered by the absence of cellular and in vivo models specifically targeting this form of autophagy. This project proposal aims at solving this problem through the generation, characterization, and study of a new mouse model conditionally and specifically deficient for LC3-independent autophagy. The experimental model is based on the expression of a truncated form of FIP200 unable to interact with autophagy receptors, but still proficient in LC3-dependent autophagy. The proposed project integrates the study of mutations in autophagy receptors identified in patients with inflammatory pathologies to finally reveal and characterize the pathophysiological relevance of unconventional autophagy.