Autophagy in the regulation of pathogen replication and adaptive immunity - PubMed (original) (raw)

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Autophagy in the regulation of pathogen replication and adaptive immunity

Felix Randow et al. Trends Immunol. 2012 Oct.

Abstract

Autophagy is an evolutionarily conserved homeostatic process by which cells deliver cytoplasmic material for degradation into lysosomes. Autophagy may have evolved as a nutrient-providing homeostatic pathway induced upon starvation, but with the acquisition of cargo receptors, autophagy has become an important cellular defence mechanism as well as a generator of antigenic peptides for major histocompatibility complex (MHC) presentation. We propose that autophagy efficiently protects against microbes encountering the cytosolic environment accidentally, for example, upon phagosomal damage, whereas pathogens routinely accessing the host cytosol have evolved to avoid or even benefit from autophagy.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Restriction of pathogens by macroautophagy and their escape. Autophagosomes are formed with the help of two ubiquitin-like systems (ATG8/LC3 and ATG12) and their formation and degradation is guided by phosphatidylinositol-3 (PI3) kinase complexes. The ATG8/LC3 ligase complex ATG5–ATG12–ATG16L1 conjugates ATG8/LC3 to the isolation membrane or phagophore and is then recycled from the outer autophagosomal membrane with ATG8/LC3. Upon fusion with lysosomes, the inner autophagosomal membrane and its content, including pathogens, is degraded. Viruses interfere with this process and either block autophagosome formation or degradation by interacting with ATG6/BECLIN-1, which is contained in autophagosome forming PI3 kinase complexes (VPS34 as PI3 kinase, VPS15, ATG6/BECLIN-1 and ATG14L) and autophagosome degrading (VPS34, VPS15, ATG6/BECLIN-1 and UVRAG) or degradation blocking (VPS34, VPS15, ATG6/BECLIN-1, UVRAG and Rubicon) PI3 kinase complexes.

Figure 2

Figure 2

How autophagy and LC3-assisted phagocytosis defend cells against infection. Synergistic lines of defence prevent the entry of pathogens into the cytosol of host cells. (a) LC3-assisted phagocytosis is triggered by Toll-like receptors (TLRs) and potentially other pattern recognition receptors (PRRs) in response to microorganisms that are taken up by phagocytosis or that have actively invaded nonphagocytic cells. LC3-assisted phagocytosis requires a subset of autophagy genes for the labelling of phagosomes with ATG8/LC3, which promotes their lysosomal delivery and the efficient killing of vesicular pathogens. (b) Damage to the limiting membrane of the pathogen-containing vesicle, either accidental or caused by pathogens attempting to escape from the vesicle, exposes the cytosol to glycans previously hidden inside the vesicle. (c) Cytosol-accessible glycans are detected by the danger receptor galectin-8, which, by recruiting the cargo receptor NDP52 (nuclear dot protein 52), triggers autophagy. (d) Pathogens having escaped galectin-8-induced autophagy are met by yet another layer of PRRs in the cytosol. (e) A yet-to-be-identified E3 ubiquitin ligase causes the ubiquitin-coating of invading bacteria. It remains to be established whether this ligase only targets membrane-associated or also free-floating bacteria, whether it is a PRR, and also whether its substrate is of bacterial or host origin. (f) Ubiquitin-coated bacteria are targeted for autophagy by three apparently non-redundant cargo receptors, that is, NDP52, p62, and optineurin.

Figure 3

Figure 3

Antigen for major histocompatibility complex (MHC) class II presentation can be provided by phagocytosis or macroautophagy. Cytosolic pathogens are delivered to MHC class II containing compartments (MIICs) via macroautophagy for antigen loading. Extracellular pathogens reach this MHC class II loading compartment via endocytosis, which might be in some instances be facilitated by ATG8/LC3 coupled to the phagosome.

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