Autophagy is crucial for the preservation of homeostasis. It can be a non-selective 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 be exclusively mediated by the LC3-dependent recruitment of the cargo to the growing phagophore, but new studies demonstrated existence of an alternative LC3-independent pathway. Our lab recently provided physiological relevance to this pathway by showing that its inactivation causes TNF-mediated embryonic lethality and inflammatory skin lesions in the adult mouse. The study of this emerging pathway is however 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.