Autophagy in immunity and inflammation

Abstract

Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

Figure 1. Schematic overview of autophagy and its regulation.

Overview of the autophagy pathway. The top right box shows a model of our current understanding of the molecular events involved in membrane initiation, elongation and completion of the autophagosome. The major membrane source is thought to be the endoplasmic reticulum (ER), although several other membrane sources, such as mitochondria and the plasma or nuclear membrane, may contribute. After induction of autophagy, the ULK1 complex (ULK1–ATG13–FIP200–ATG101) (downstream of the inhibitory mTOR signalling complex) translocates to the ER and transiently associates with VMP1, resulting in activation of the ER-localized autophagy-specific class III phosphatidylinositol-3-OH kinase (PI(3)K) complex, and the phosphatidylinositol-3-phosphate (PtdIns(3)P) formed on the ER membrane recruits DFCP1 and WIPIs. WIPIs and the ATG12–ATG5–ATG16L1 complex are present on the outer membrane, and LC3–PE is present on both the outer and inner membrane of the isolation membrane, which may emerge from subdomains of the ER termed omegasomes. The cellular events that occur during autophagy are depicted in the bottom diagram, including the major known cellular and microbial proteins that regulate autophagy initiation, cargo recognition and autophagosome maturation. Only those cellular proteins known to be adaptors for targeting microbes are shown; other proteins (not shown) also function in cargo recognition of mitochondria and other organelles. CMV, cytomegalovirus; DAMP, danger-associated molecular pattern; DAP, death-associated protein; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HSV-1, herpes simplex virus 1; KSHV, Kaposi's sarcoma-associated herpesvirus; LIR, LC3-interacting region (motif); LPS, lipopolysaccharide; MDP, muramyl dipeptide; Pam₃Cys₄, a synthetic TLR2 agonist; PAMP, pathogen-associated molecular pattern; PERK, an eIF2α kinase; PGN, peptidoglycan; PRGP-LE, a peptidoglycan-recognition protein; PRR, pathogen-recognition receptor; ROS, reactive oxygen species; Ub, ubiquitin; UBA, ubiquitin-associated domain; UBZ, ubiquitin-binding zinc finger; v-FLICE, viral FLICE.

Figure 2. Possible autophagy-protein-dependent pathways of pathogen degradation.

Possible pathways involving the autophagy machinery by which viruses, bacteria (and damaged membranes of bacteria-containing vacuoles) and parasites may be targeted to the lysosome. Adaptor refers to the proteins shown in the cargo-recognition box in Fig. 1; however, as yet undiscovered adaptors may be involved in pathogen recognition, and pathogen targeting may involve ubiquitin-dependent or -independent mechanisms.

Figure 3. Functions of the autophagy pathway and/or proteins in immunity.

A summary of the known functions of the autophagy pathway and/or proteins in adaptive and innate immunity, and as effectors during infection.

Figure 4. Autophagy/autophagy proteins act to achieve a balance between activation and inactivation of innate immune signalling.

A general model in which the levels of autophagy and autophagy proteins control disease in response to stressors. Normal autophagy protein function (green) contributes to balanced inflammatory and metabolic responses, resulting in protection against disease. Altered autophagy protein function (red) results in maladaptive inflammatory and metabolic responses, increased inflammation and more severe disease.

Figure 5. The link between mutations in autophagy regulators and the chronic inflammatory disorder Crohn's disease.

An overview of the many possible mechanisms by which defects in autophagy and autophagy protein function may contribute to the pathogenesis of a type of inflammatory bowel disease, Crohn's disease. A micrograph of a human small intestine from a patient with Crohn's disease is shown (centre), demonstrating the severe transmural inflammation that is characteristic of this disease. The postulated mechanisms by which defects in autophagy protein function might contribute to the development or perpetuation of intestinal inflammation are based on studies in vitro and animal models. There is no direct evidence that autophagy defects contribute to human Crohn's disease, although mutations in three autophagy-related genes, ATG16L1, NOD2 and IRGM, are known to enhance risk of the disease. E, epithelium; IgM, immunoglobulin M; L, lumen; LA, lymphoid aggregates; TM, thickened muscle. Scale bar, 200 μm.