Non-canonical autophagy mediates immunosuppression during challenge

Abstract Autophagy is an evolutionarily conserved, catabolic pathway that lies at the intersection of homeostasis and host immune response. The autophagy machinery functions in a multitude of biological pathways, including the recycling of intracellular nutrients during starvation or stress (macroautophagy), the quality control removal of damaged proteins or organelles (aggrephagy, mitophagy), or the degradation of and host defense to extracellular threats, such as pathogens or dying cells. However, the non-canonical roles of the autophagy machinery are a critical node in the immune response to invasive pathogens, as well as prevention of autoimmunity. We have identified a form of non-canonical autophagy termed LC3-associated phagocytosis (LAP), a phenomenon in which phagosomes containing engulfed particles, including pathogens and dying cells, recruit certain elements of the autophagy pathway to facilitate phagosome maturation, digestion of cargo, and modulation of innate immunity. Importantly we have characterized Rubicon as a LAP-specific, autophagy-independent molecule, allowing the study of the unique role of LAP. We recently demonstrated that defects in LAP, but not canonical autophagy, result in a lupus-like disease with age. Using Rubicon−/− mice, we are now investigating the role of LAP in other autoimmune disease onset and progression. Our evidence clearly indicates that LAP is critical in the maintenance of immunotolerance in a variety of inflammatory diseases, including type 1 diabetes, allergic asthma, and atopic dermatitis. Mechanistically, we have begun to dissect the molecular pathways, such as metabolism, that LAP modulates in order to achieve immunosuppression. This research was supported by the NIEHS.