Autophagy is a cellular degradation process that regulates protein homeostasis, removes defective organelles and targets intracellular pathogens for lysosomal destruction. Defects in autophagy may be detrimental and have been linked to several human diseases. Recent in vitro studies have reported on a new unconventional autophagy pathway that is functionally distinct from classical autophagy, however, it remained unclear whether this process had any (patho)physiological functions in vivo. We previously discovered that this unconventional autophagy pathway is critical to prevent inflammatory skin disease in mice by repressing TNF-mediated keratinocyte cell death. We now collected preliminary data indicating that unconventional autophagy has an even broader role in preventing skin pathogenesis by acting as a brake on interferon production and by repressing ZBP1-induced cell death. Mice harboring a keratinocyte-specific defect in unconventional autophagy have a clear interferon signature and consequently express high levels of ZBP1, which induces massive inflammatory cell death in the skin. This project consists in characterizing this inflammatory skin disease and determining how unconventional autophagy normally represses this detrimental interferon response. In addition, we will study how ZBP1 is targeted by unconventional autophagy to suppress its cytotoxic activity.