Mucosal surfaces are the first line of contact for most pathogens, with the respiratory, intestinal, and reproductive tracts representing the major exposure sites to a variety of mucosal pathogens. Additionally, the mucosal surfaces possess a numerically vast and taxonomically diverse resident microbiota. Therefore, these mucosal sites must integrate a finely tuned immune network to balance the protection against pathogens and tolerance to commensal microbes. Autophagy is considered a critical modulator of the multifaceted and complex mucosal immunity.

Macroautophagy or canonical autophagy is a cellular process evolutionarily conserved from yeast to mammals [1]. Autophagy is characterized by the formation of LC3/autophagy-related gene 8 (ATG8)+ double membrane–bound structures known as autophagosomes, which capture cytoplasmic proteins and organelles and transport these cargos to the lysosome for degradation [1]. This sensu stricto canonical autophagy is mediated by over 20 core autophagy proteins, with a large number of additional proteins participating in specific biological actions of autophagy 1, 2, 3. Mammalian autophagy is triggered by a preinitiation complex composed of a core of ULK1/2, ATG13, and FIP200 proteins. The preinitiation complex activates the initiation complex, consisting of ATG14, BECLIN1, VPS34, and VPS15, which generates the isolation membrane that elongates into the double membrane–bound autophagosome. This elongation process is facilitated by two ubiquitin-like protein conjugation systems, composed of ATG7, ATG3, ATG5, ATG16L1, and ATG12 to conjugate LC3 family members to phosphatidylethanolamine, creating LC3-II from LC3-I [3]. Subsequently, LC3-II–positive autophagosomes fuse with lysosomes to form autophagolysosomes where the cargo is degraded 4, 5. EPG5 is required for the proper function of autophagolysosomes to ensure the degradative process of autophagy [6].

Many past studies attributed the infection outcome of loss of core autophagy genes to the loss of canonical autophagy, since the loss of core autophagy proteins abolishes autophagosome formation and autophagic function. As a function of canonical autophagy, autophagic degradation of microbes, which is termed xenophagy, was thought to be the key mechanism of how autophagy genes contribute to infection and immunity. However, it has become increasingly evident that the loss of individual core genes also results in gene-specific changes in infection and inflammatory outputs. In recent years, efforts have been made to define the canonical versus gene-specific mechanisms of autophagy genes in physiologically relevant processes [3]. We refer to canonical autophagy, requiring all essential autophagy genes, to distinguish it from other cellular processes that require certain but not the entire set of autophagy genes, for which we will term ‘autophagy gene-specific functions.’ These autophagy gene–specific functions include secretion 7, 8, 9, control of intracellular viral, parasite and bacterial replication 10••, 11, LC3-associated phagocytosis or conjugation of ATG8/LC3 to single membranes 12, 13, and immune regulation 1, 14, 15••, 16, all of which can be distinguished genetically from canonical autophagy. Therefore, it is practical to dissect how individual autophagy genes exert molecular control of immune and inflammatory pathways, and whether these genes regulate inflammation through effects on canonical autophagy or through autophagy-independent mechanisms unique to one or more autophagy genes. This is significant because a number of therapeutic approaches inhibiting or activating autophagy are in development 17, 18. Many canonical autophagy and autophagy gene–specific functions participate in modulating mucosal immunity and defending against mucosal pathogens. We aim to provide a representative overview of in vitro and in vivo mechanistic knowledge on how the biological functions of autophagy genes contribute to the establishment of the mature mucosal immune system and host responses to important mucosal pathogens (Table 1).