Autophagy and intestinal homeostasis

Abstract

Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract.

Figure 1

Stages of the autophagy pathway. (a) Induction of autophagy is mediated by the unc51-like kinase (ULK) complex, which is regulated by mammalian target of rapamycin (mTOR). (b) Nucleation is mediated by class III phosphatidyl inositol 3-kinase (PI3K). Nucleation produces an isolation membrane (phagophore). (c) The double membrane is extended by the ubiquitin-like conjugation systems of LC3 and Atg12. LC3 is conjugated to phosphatidylethanolamine (PE) and is incorporated into the autophagosome. (d) Mature autophagosomes fuse with lysosomes to produce autolysosomes.

Figure 2

Potential cellular targets of autophagy proteins in the intestine. Autophagy proteins are required for a variety of cellular functions that may be relevant to the intestine. These functions include lymphocyte development and survival, antigen presentation by dendritic cells, xenophagy and cytokine secretion by monocyte-derived cells, and antimicrobial peptide secretion by Paneth cells.