Autophagy and selective deployment of Atg proteins in antiviral defense

Abstract

Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy-related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors.

Fig. 1.

Cooperation between Atg proteins, triggers and adaptors in antiviral defense. (A) Distinct triggers (in red) and set subsets of Atg proteins (in blue) interact with sensors and adaptors (in gray) in order to perform a diverse set of effector functions (in green). In (B), the canonical autophagy machinery selectively removes Sindbis viral particles in infected neurons via the adaptor proteins SMURF1 and p62. The p62 interacts with Sindbis viral capsids, facilitating efficient targeting and clearance of viral proteins. (C) In MNV infection, a subset of Atg proteins including Atg5, Atg7, Atg12 and Atg16L1 disrupt viral replication complexes via an IFN-γ-dependent mechanism. In this case, the term ‘adaptor’ may not be relevant because this Atg-dependent antiviral mechanism does not involve autophagosomes. (D) The canonical autophagy machinery also facilitates removal of damaged mitochondria. This depends on mitochondrial adaptors as well as other unknown triggers and sensors.

Fig. 2.

Role of the autophagy machinery in innate immune signaling. In endosomal viral recognition through TLRs, autophagy facilitates the transport of viral ligands to the signaling endosome where TLRs recognize viral PAMPs and initiate production of pro-inflammatory cytokines and type I interferons. In contrast, autophagy plays an important role in negatively regulating cytosolic viral recognition. Autophagy indirectly regulates innate antiviral signaling by removal of innate immune signaling complexes.

Fig. 3.

TLRs and autophagy in innate immunity. (A) Cell wall components of Gram-positive bacteria and yeast are recognized by TLR2 whose activation triggers the association of LC3 with the phagosomal membrane and promotes phagolysosomal fusion. Phagocytosis of dead cells through recognition of surface PtdSr by Tim4 also utilizes LAP. LAP is also critical for processing and presentation of HSV antigens for MHC II by DCs. (B) Several TLRs are known to induce autophagy. (C) In pDCs, autophagy enables TLR7 recognition of cytosolic virus replication products or cytosolic viral genomes, resulting in both type I interferons and proinflammatory cytokine production (orange lines). In addition, TLR9 signaling for type I interferon production requires Atg5, possibly through the LAP-dependent signaling pathway (dotted green lines). Cytokine induction downstream of TLR9 occurs independently of Atg5 (solid line).