Autophagy genes in immunity

Abstract

In its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane-bound autophagosome and delivered to the lysosome for degradation. This pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type I interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. Most of these links have emerged from studies in which genes encoding molecules involved in autophagy are inactivated in immune effector cells. However, it is not yet known whether all of the critical functions of such genes in immunity represent 'classical autophagy' or possible as-yet-undefined autophagolysosome-independent functions of these genes. This review summarizes phenotypes that result from the inactivation of autophagy genes in the immune system and discusses the pleiotropic functions of autophagy genes in immunity.

Figure 1

The autophagy pathway and its regulation. The autophagy pathway proceeds through a series of stages, including nucleation of the autophagic vesicle, elongation and closure of the autophagosome membrane to envelop cytoplasmic constituents, docking of the autophagosome with the lysosome, and degradation of the cytoplasmic material inside the autophagosome. Vesicle nucleation depends on a class III PI(3)K complex that contains various proteins (in light yellow box at right), as well as additional proteins that regulate the activity of this complex (such as rubicon, UVRAG, Ambra-1 and Bif-1). Vesicle elongation and completion involves the activity of two ubiquitin-like conjugation systems (light blue box at right). The autophagy pathway is positively regulated (green box at left) and negatively regulated (red box at left) by diverse environmental and immunological signals. TNF, tumor necrosis factor; PE, phosphatidylethanolamine; Gly, glycine; E1 and E2, ligases for ubiquitin-like conjugation systems.

Figure 2

Immunological processes involving autophagy. The colored boxes present five immunological processes that, on the basis of data available at present, involve classical autophagy. MIIC, MHC class II loading compartment.

Figure 3

Immunological processes involving autophagy genes. The colored boxes present six immunologic processes that involve various autophagy genes but that are not yet proven to involve classical autophagy.

Figure 4

Possible mechanisms by which alterations in autophagy may be involved in the pathogenesis of human Crohn’s disease. The colored boxes present four potential mechanisms by which the mutation of an autophagy gene could contribute to Crohn’s disease, proposed on the basis of studies of model organisms in which various autophagy genes have been mutated in various cell types (boxes at bottom). So far, only ATG16L1 and IRGM1 have been linked to susceptibility to Crohn’s disease. ROS, reactive oxygen species.