Autophagy, immunity and human disease

Abstract

Purpose of review: To give an overview of autophagy and its effects on innate and adaptive immunity and touch on some of the roles of autophagy in disease.

Recent findings: Precise regulation of autophagy is necessary to maintain metabolic equilibrium, immune homeostasis, delineate cell fate and influence host cell responses to cytosolic pathogens. A growing number of studies have implicated that inactivation of autophagy-selective responses contributes to inflammatory disorders, neurodegeneration and cancer, but the precise steps at which disease-associated autophagy-related (ATG) genes affect autophagy pathways is unknown at present.

Summary: In eukaryotic cells autophagy is constitutively active at low levels, whereas significant up-regulation occurs in response to a multitude of stresses. Autophagy has achieved notoriety as a perturbed biological process in many disease states and an exponential increase of studies attribute roles for autophagy in innate and adaptive immunity. Understanding how individual disease-associated ATG genes function will lead to a better understanding of and potentially novel therapies for treating the diseases in which they are involved.

Figure 1

Building the autophagosome. The early stages of autophagosome formation are better understood than the late stages. 1. Initiation: autophagy is induced by an upstream signal. Nucleation of the isolation membrane occurs through the action of the Atg14-Beclin1-hVPS34 complex. This membrane may be derived from endoplasmic reticulum (ER). 2. Elongation: The phagophore enlarges to form a double membrane organelle. Atg16L1/Atg5-Atg5 acts as an E3 enzyme, converting LC3 I to lipidated LC3 II. Atg4 reverses LC3 II to LC3 I by removing phophatidylethanolamine (PE). 3. Closure: Closure of the elongating phagophore results in the autophagosome. The exact mechanism of closure is unknown but LC3 is necessary for closure of the phagophore. 4. Maturation: once the autophagosome has formed it must be moved to the perinuclear region of the cells for fusion with lysosomes. Both dynein and microtubules are necessary for this process, but the regulation of this process is unknown. Once the autophagosome has fully closed the Atg16 complex rapidly dissociates, but LC3 remains attached. It is possible that LC3 mediates an interaction between dynein and microtubules to facilitate translocation of the autophagosome to the lysosomal region of the cell. Fusion with lysosomal organelles causes acidification of the autophagosome converting it into the degradative, single membrane autolysosome. The UVRAG-Beclin1-VPS34 complex can promote maturation of the autophagosome, while the Rubicon-UVRAG-Beclin1-VPS34 complex can suppress maturation of the autophagosome. Coding variants identified from GWAS studies are shown inset. The ATG16L1 allele T300A is associated with susceptibility to Crohn's disease and the ATG5 C/T coding variant, where T is the minor allele, is associated with susceptibility to systemic lupus erythematosus. CC-coiled-coil domain.

Figure 2

Autophagy is involved in innate and adaptive immunity. Autophagy is involved in the regulation of the inflammasome (innate immunity). The inflammasome is activated by numerous ligands leading to the activation of Caspase 1 and the secretion of the proinflammatory cytokines IL-1β and IL18. Autophagy may degrade the inflammasome in order to dampen the inflammatory response. Furthermore, a coding variant in the NLRP3 region is a Crohn's disease risk factor. Autophagy is involved in MHC II antigen presentation (adaptive immunity). Antigen in the cytosol is captured by the autophagosome, which merges with the MHCII loading compartment (MIIC) where it is processed and presented on MHC II.

Figure 3

Autophagy and cancer. Autophagy is a major component of the stress response and is involved in tumour suppression. Under normal conditions cytosolic p53 can suppress oncogenic potential by triggering apoptosis or senescence. Cytosolic p53 can also transactivate genes that induce autophagy. Autophagy degrades the pool of p53 in order to alleviate its inhibitive effects. Nuclear, transactivation-dependent effects of p53 and cytosolic, transcription independent inhibition of autophagy pathways likely act in unison to coordinate p53 mediated stress adaptation. Oncogene induced activation of autophagy can induce senescence in vitro. The ubiquitin binding protein p62 links autophagy to the proteosome. In autophagy deficient tumour cells, p62 accumulates in response to metabolic stress. p62 is likely turned-over by autophagy and its accumulation alone is sufficient to promote tumourigenesis via altered NFκB regulation. Ub -ubiquitin., ROS-Reactive oxygen species.