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  • Review Article
  • Published:

Autophagy in infection, inflammation and immunity

Key Points

  • Autophagy is a fundamental eukaryotic homeostatic pathway that affects innate and adaptive immunity. Autophagic responses are integrated with pattern recognition receptor and cytokine signalling.

  • Autophagic receptors, termed sequestosome 1-like receptors, target intracellular microorganisms for autophagy via ubiquitin and galectin tags, and they represent a new class of pattern recognition receptors. Intracellular pathogens have evolved elaborate strategies to prevent, neutralize or commandeer autophagy to support their own survival.

  • Autophagy is a potent anti-inflammatory process that inhibits inflammasome activation and that modulates type I interferon responses. Autophagy affects the secretion of inflammatory and antimicrobial mediators.

  • Autophagy enhances conventional phagosome maturation, affects antigen presentation, and influences T cell homeostasis and T helper cell polarization.

  • Genetic predisposition and physiological links exist between autophagy and infectious, inflammatory and autoimmune diseases in humans.

Abstract

Autophagy is a fundamental eukaryotic pathway that has multiple effects on immunity. Autophagy is induced by pattern recognition receptors and, through autophagic adaptors, it provides a mechanism for the elimination of intracellular microorganisms. Autophagy controls inflammation through regulatory interactions with innate immune signalling pathways, by removing endogenous inflammasome agonists and through effects on the secretion of immune mediators. Moreover, autophagy contributes to antigen presentation and to T cell homeostasis, and it affects T cell repertoires and polarization. Thus, as we discuss in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.

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Figure 1: Four principal roles of autophagy in immunity.
Figure 2: Autophagy-mediated clearance of intracellular pathogens.
Figure 3: Autophagy controls inflammatory processes.

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Acknowledgements

We apologize to our colleagues whose work or specific studies have not been cited. This is not a reflection of lack of interest on the authors' part or on the significance for the field but was dictated by the article scope and reference number limitations. V.D. is supported by US National Institutes of Health grant AI042999 and by a grant from the Bill and Melinda Gates Foundation.

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Glossary

Macroautophagy

The autophagy-related protein (ATG)-dependent pathway, sequestering cargo into autophagosomes that fuse with lysosomes, in which the cargo is degraded. Proteins, organelles (such as mitochondria) and invading microorganisms are selectively degraded by macroautophagy. Bulk cytoplasmic autophagy occurs as a starvation response.

Microautophagy

Lysosomal import and degradation of small portions of the cytoplasm that is independent of autophagy-related proteins (ATGs), and that is often manifested as invaginations of the lysososomal membrane into the lysosomal lumen.

Chaperone-mediated autophagy

The import and degradation of soluble cytoplasmic proteins by chaperone-dependent direct translocation across the lysosomal membrane.

Non-canonical autophagy

Macroautophagy that has been reported to occur independently of one or more components of the autophagy-related protein (ATG) system. It should not be confused with non-canonical functions of ATGs, which refers to the participation of individual ATG factors in processes other than autophagy.

SNARE

(Soluble NSF attachment protein receptor). A member of a class of proteins that catalyse membrane fusion and thus regulate organelle identity and vesicular trafficking. The membrane fusion occurs through the formation of a cognate Qa-, Qb-, Qc- and R-SNARE four-helix bundle, which consists of SNAREs on donor and acceptor membranes.

Mammalian target of rapamycin

(mTOR). A serine/threonine protein kinase that regulates cell growth and metabolism. mTOR is stimulated by growth factor receptor and phosphatidylinositol-3,4,5-phosphate-dependent signalling. It responds to the availability of nutrients (for example, amino acids). Active mTOR inhibits autophagy via the serine/threonine protein kinase ULK1.

AMP-activated protein kinase

(AMPK). A sensor of cellular energetic state. It is activated by increased AMP levels which indicate decreased energy status following hypoxia or nutrient deprivation.

Xenophagy

The selective degradation of intracellular pathogens (such as bacteria or viruses) through macroautophagy.

LC3-associated phagocytosis

(LAP). A shared pathway that involves conventional phagocytosis and autophagy at the maturation stage that is mediated by the recruitment of the autophagy protein LC3 (which is the mammalian homologue of yeast ATG-8). LAP results in a more robust phagolysosome, which can also function as a specialized signalling compartment or an antigen-presentation compartment.

Sequestosome 1-like receptors

(SLRs). These are autophagic adaptors that recognize microbial targets and that link them to autophagy machinery by binding to mammalian autophagy-related protein 8 (ATG-8) proteins (for example, autophagy related LC3 proteins and γ-aminobutyric acid receptor-associated proteins (GABARAPs)).

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract, but is most common in the terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation.

Ubiquitin-binding domains

(UBDs). Domains that have different specificities for ubiquitin chains: UBA, which is found in sequestosome 1, favours K63 polyubiquitin chains; UBZ, which is found in nuclear dot protein 52 (NDP52), binds to monoubiquitin and polyubiquitin; and UBAN, which is found in optineurin, has specificity for linear ubiquitin chains.

LC3-interacting region motif

(LIR motif). Canonical LIR motif, which is X/(D,E,S,T)-X/(D,E,S,T)-X/(D,E,S,T)-W/F/Y-X/(D,E,S,T)-X-L/I/V, where X/(D,E,S,T) indicates that any amino acid (X) is allowed but that acidic (D,E) or phosphorylatable amino acids (S,T) are often present. Aromatic residues (W/F/Y) occupy the aromatic pocket and aliphatic side chains (L/I/V) occupy an aliphatic pocket present in all autophagy- related protein 8 (ATG-8) homologues. The LIR motif forms an intermolecular β-sheet with ATG-8 homologues, not discriminating between mammalian paralogues of yeast ATG-8.

CLIR motif

A variant of the LC3-interacting region (LIR) motif (L-V-V), which is found in nuclear dot protein 52 (NDP52). The CLIR motif binds to the LIR-interacting region in LC3C. The CLIR motif lacks the signature aromatic residue of the LIR motif. Instead, it makes compensatory hydrophobic contacts with LC3C.

Leucine-rich repeat

(LRR). A domain that is often found in pattern recognition receptors and that is involved in pathogen-associated molecular pattern recognition. LRRs are repeats of L-X-X-L-X-L-X-X-N-X-L or L-X-X-X-L-X-L-X-X-C-X-X-L motifs (where X represents any amino acid), which form a horseshoe or solenoid tertiary structure.

Mitophagy

A special form of autophagy by which mitochondria (in a damaged or depolarized state) are engulfed by autophagosomes and degraded.

Exocyst

An evolutionarily conserved protein complex that consists of eight subunits and that is best known for targeting exocytic vesicles to sites of docking and fusion at the plasma membrane. It also functions as a protein complex assembly platform.

Citrullinated antigens

Citrullin is enzymatically generated from arginine residues by peptidylarginine deaminase, which is an enzyme that may be enriched in autophagosomes. The presence of autoantibodies in patients with rheumatoid arthritis correlates with the levels of citrullinated antigens (such as vimentin).

Epithelial-to-mesenchymal transition

A reversal of the mesenchymal-to-epithelial transition that occurs during development. Epithelial-to-mesenchymal transition or the dedifferentiation of epithelial cells can have normal physiological roles (such as in wound healing) or can be associated with fibrotic pathologies and cancer.

miRNA response elements

Sequences on RNA transcripts that have partial complementarity to microRNAs (miRNAs). miRNA binding to the response elements typically leads to repression of target gene expression.

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Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13, 722–737 (2013). https://doi.org/10.1038/nri3532

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