Autophagy, nutrition and immunology

Abstract

Turnover of cellular components in lysosomes or autophagy is an essential mechanism for cellular quality control. Added to this cleaning role, autophagy has recently been shown to participate in the dynamic interaction of cells with the surrounding environment by acting as a point of integration of extracellular cues. In this review, we focus on the relationship between autophagy and two types of environmental factors: nutrients and pathogens. We describe their direct effect on autophagy and discuss how the autophagic reaction to these stimuli allows cells to accommodate the requirements of the cellular response to stress, including those specific to the immune responses.

Figure 1. Types of autophagy in mammalian cells

Three types of autophagy co-exist in all mammalian cells. Macroautophagy involves the sequestration of regions of the cytosol inside double membrane vesicles that become degradative compartments upon fusion with the lysosomes. Both in bulk and selective macroautophagy can take place. Specific examples of selective macroautophagy are highlighted on the left. Microautophagy occurs when cytosolic components are directly engulfed by lysosomes through invaginations of the lysosomal membrane. Recent studies support that microautophagy occurs in late endosomes both in bulk and in a selective manner depending on the interaction of the substrates with a chaperone. Chaperone-mediated autophagy, the third type of mammalian autophagy, initiates through the recognition by a chaperone of a targeting motif in the cytosolic protein to be degraded. The chaperone/substrate complex reaches then the lysosome surface and the substrate is internalized through a translocation complex in the lysosomal membrane.

Figure 2. Interplay between autophagy, nutrients and the cellular energetic balance

Autophagy contributes to the catabolism of different essential molecules provided by the diet. In the absence of nutrients, autophagy facilitates breakdown of intracellular proteins to facilitate the amino acids required to maintain protein synthesis under those conditions. New affluence of amino acids with the diet represses autophagic function. Cells can also utilize macroautophagy to mobilize intracellular lipid stores (left) and glycogen (right) to generate energy when nutrients are scarce. Breakdown of intracellular stores by macroautophagy can also occur in response to a high affluence of lipids or glucose. This mechanism is used by cells to control the size of intracellular stores and prevent their massive accumulation.

Figure 3. Autophagy and the immune system. Pathogen Killing

Engagement of plasma membrane or intracellular pattern recognition receptors (PRR), such as toll like receptors can activate macroautophagy to induce the degradation and killing of intracellular pathogens. Bacteria that escape from the phagosomes into the cytosol can be targeted by macroautophagy adaptor proteins (AP), such as p62 or optoneruin, and incorporated into autophagosomes. Phagosomes containing pathogens can also be incorporated into nascent autophagosomes. In both cases, autophagosomes fuse with lysosomes to degrade microorganisms contained in them. Furthermore, macroautophagy helps ensure pathogen killing through the delivery of proteins with microbicidal activity into the autolysosomes. Contributing to the overall regulation of the phagocytic response, macroautophagy can also delivered PRR ligands (PPRL) to intracellular PRR-containing endosomes. Antigen Presentation: Cytosolic proteins can be delivered into late endosomes for processing and subsequent loading of peptides into MHC class II molecules, which will eventually reach the plasma membrane to present those peptides to CD4+ T cells. Three forms of autophagy, macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) contribute to the delivery of those proteins into the class II compartment in antigen presenting cells. T lymphocytes function: Macroautophagy allows the presentation of self-peptides in MCH class II molecules by epithelial cells in the thymus and regulates the positive and negative selection of thymocytes, contributing to the shaping of the T cell repertoire. Furthermore, in peripheral T cells basal macroautophagic activity is crucial to maintain proper organelle homeostasis, whereas activation-induced macroautophagy regulates the energy metabolism and controls cell proliferation and survival of T cells.

Figure 4. Autophagy, aging and immunosenescence

Both macroautophagy and CMA activity decrease with age in most cell types and could contribute directly or indirectly to immunosenescence. Direct effect: Reduced macroautophagic activity can compromise the cellular response to pathogens and self-recognition by the immune system by interfering with antigen presentation. The age-dependent decline in CMA could also contribute to inadequate antigen presentation in elders. Indirect effect: Compromised autophagic function with age may contribute to deficient maintenance of the cellular energetic balance and inability to adapt to the high energetic demands of the immune response.