Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors

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Autophagy is rapidly developing into a new immunological paradigm. The latest links now include overlaps between autophagy and innate immune signaling via TBK-1 and IKKα/β, and the role of autophagy in inflammation directed by the inflammasome. Autophagy's innate immunity connections include responses to pathogen and damage-associated molecular patterns including alarmins such as HMGB1 and IL-1β, Toll-like receptors, Nod-like receptors including NLRC4, NLRP3 and NLRP4, and RIG-I-like receptors. Autophagic adaptors referred to as SLRs (sequestosome 1/p62-like receptors) are themselves a category of pattern recognition receptors. SLRs empower autophagy to eliminate intracellular microbes by direct capture and by facilitating generation and delivery of antimicrobial peptides, and also serve as inflammatory signaling platforms. SLRs contribute to autophagic control of intracellular microbes, including Mycobacterium tuberculosis, Salmonella, Listeria, Shigella, HIV-1 and Sindbis virus, but act as double-edged sword and contribute to inflammation and cell death. Autophagy roles in innate immunity continue to expand vertically and laterally, and now include antimicrobial function downstream of vitamin D3 action in tuberculosis and AIDS. Recent data expand the connections between immunity-related GTPases and autophagy to include not only IRGM but also several members of the Gbp (guanlyate-binding proteins) family. The efficacy with which autophagy handles microbes, microbial products and sterile endogenous irritants governs whether the outcome will be with suppression of or with excess inflammation, the latter reflected in human diseases that have strong inflammatory components including tuberculosis and Crohn's disease.

Highlights

► Autophagy is a developing immunological paradigm with vertical and lateral connections in innate immunity. ► Sequestosome 1/p62-like adaptors (SLRs) serve both as autophagic adaptors and innate immunity signaling platforms. ► Balance between autophagic clearance via SLRs and their and other inflammatory signaling determines degree of collateral inflammatory damage. ► Interactions between autophagy and inflammasome involve both suppression of inflammasome activation and enhancement through the autophagy-based unconventional secretion of inflammasome substrates.

Introduction

The sensu stricto autophagy (often referred to as macroautophagy) is a ubiquitous eukaryotic process dependent on Atg factors and internal membrane formation in the cytoplasm that form unique organelles called autophagosomes [1]. Autophagosomes capture diverse cytoplasmic cargo with a variety of end purposes: (a) quality control of disused or defunct organelles such as irreversibly depolarized or leaky mitochondria; (b) removal of toxic macromolecular aggregates too large for handling by smaller capacity or single-molecule-handling proteolytic systems of the cell (e.g. proteasome); (c) digestion of bulk cytoplasm expressly to replenish amino acids and energy during starvation or growth factor withdrawal; (d) acting on or in concert with the molecular machineries and organelles at the interface between cell survival and cell death; and (e) controlling and acting as an effector or a regulator of innate and adaptive immunity and inflammation, which is the focus of this review.

One of the first reviews on this topic, written half a decade ago by the author [2] referred to several studies that have appeared at the time, suggesting rather gingerly a potential role for autophagy in immunity. Five to six years later, the immunological roles of autophagy have become one of the better-established physiological functions of autophagy, as summarized in a number of recent comprehensive reviews [3, 4, 5]. The anti-inflammatory role of autophagy and its anti-microbial action [4] have not remained ‘unnoticed’ by prospective pathogenic microbes in the process of their adaptation to a potentially susceptible host. Many highly successful pathogens have evolved mechanisms to counter or harness autophagy attesting to the significance of autophagy as a bona fide antimicrobial defense [5]. Autophagy roles in immunity have been established through in vitro, ex vivo, and in vivo models [4, 5]. Importantly, immunological autophagy, via a variety of cellular and molecular mechanisms [6••, 7, 8••], shows unequivocal genetic links to inflammatory bowel Crohn's disease [9] and tuberculosis (reviewed in [5]). The genetically established role of autophagy in human immunity is arguably the most critical evidence for the health relevance of immunological autophagy [5, 9].

The present review reflects the author's bias that the innate immunity role of autophagy is not just another physiological application of autophagy but is a key evolutionary driver and mainstream effector–regulator of autophagy that may have shaped several facets of this fundamental biological process. Another underlying theme of this opinion article is to consider autophagic adaptors [10], termed in the immunological context as sequestosome 1/p62-like receptors (SLRs) [5], as another category of pattern recognition receptors (PRRs) on par with Toll-like receptors (TLRs), Nod-like receptors (NLRs), and RIG-I-like receptors (RLRs).

Section snippets

Autophagy as an intracellular membrane trafficking pathway with potential links to inflammatory platforms

Autophagosomes are believed to emerge at least in part from the ER membranes [11] via an ER cradle model, with the autophagic phagophore (isolation membrane) being formed from or in the vicinity of a PI3P-possitive (albeit PI3P is atypical for the ER) and DFCP-positive transient omegasome structures (reviewed in [1]) (Figure 1). This likely occurs with participation of additional compartments and organelles supplying either assembly/signaling platforms, phospholipids, or membrane intermediates

Convergence of pro-inflammatory, immune, and physiological signaling pathways in control of autophagy

Much of the innate immunity signaling occurs through or involves the members of the IκB family of kinases (IKKs), which fall into two categories – canonical (IKKα, IKKβ) and IKK-related kinases (IKKɛ and TBK-1). TBK-1, a key regulator of type I interferon response to viral infections, has been shown to play a role in autophagy [22••]. TBK-1 phosphorylates optenurin, a TBK-1-interactor analogous to NEMO (IKK-γ; which serves as a platform for the canonical IKK complex). The phosphorylated

Autophagy and conventional PRRs: TLRs

Continuing along with the theme of connections between autophagy and innate immunity responses, autophagy pathway and machinery shows physical, signaling, and regulatory interactions with PRRs, such as TLRs, RLRs, NLRs, and inflammasomes [5] (Figure 3).

TLRs were historically the first class of PRRs to be connected with autophagy [5]. Autophagy is induced by signaling from TLRs as recently summarized or discussed [3, 4, 5]. Importantly, the details of how TLRs connect to autophagy have been

Autophagy and NLRs

Connections between NLR signaling and autophagy (Figure 3) exist in species from Drosophila to mammals (reviewed in [5]). Murine Nod1 and Nod2 have been reported to interact with Atg16L1 and may modulate autophagy in the context of Crohn's disease by several mechanisms [4] including influencing the localization of Atg16L1 at the point of microbial entry at the plasma membrane [27]. Intriguingly, this independently supports the model of plasma membrane as a source of Atg16L1 vesicular precursors

Autophagy and RLRs

RLRs connections with autophagy (Figure 3) are notable for the usual emphasis in published reports on the negative regulation of RLR signaling by autophagy including autophagy factors Atg5–Atg12 and Atg9 (reviewed in [3]). Atg9 has been reported to negatively regulate trafficking, assembly and activation of TBK-1 in type I interferon response elicited by intracellular double stranded DNA (dsDNA) [3]. However, in the study showing that Atg9 negatively regulates assembly of STING (stimulator of

Autophagic adaptors, SLRs, as a new class of PRRs, link autophagy and innate immunity signaling

Autophagic targets in the cytoplasm, ranging in nature, size, and complexity from protein aggregates to whole organelles are recognized and collected by proteins that act as autophagic adaptors [10]. The two principal adaptors, p62 and NBR1 (Figure 2), have been well characterized and show domain and sequence similarity [10]. These autophagic adaptors have been termed SLRs [5] to emphasize that they represent a new family of innate immunity receptors, as another category of PRRs engaged in

SLRs, antimicrobial peptides, and vitamin D3

SLRs can also act in a completely different manner to promote autophagic killing of intracellular microbes. In the case of p62, this SLR can collect cytoplasmic precursors to be converted in autolysosomes into neo-antimicrobial products [41••]. The antimicrobial peptides generated in autolysosomes or autophagolysosomes can be derived by limited proteolysis from cytosolic proteins such as ubiquitin [42••] and ribosomal proteins [41••]. Thus, autophagolysosomes can acquire additional microbicidal

DAMP signaling and autophagy

Alarmins or damage associated molecular patterns (DAMPs) represent a number of diverse cellular components that undergo a change in their intracellular localization or are released from damaged cells serving as reporters of a need to contain cell or tissue injury under sterile or septic conditions. DAMPs induce autophagy [47, 48••]. HMGB1, an alarmin [49], undergoes a stepwise displacement from the nucleus (where it is a chromatin component) into the cytoplasm with eventual extracellular

Basal autophagy prevents spurious inflammasome activation

Autophagy and inflammasome show complex functional interactions (Figure 3). DAMPs such as ATP that signal to induce K+ efflux, pore-forming toxins and ionophores (e.g. streptolysin O and nigericin), structurally diverse particulates such as silica, alum and asbestos, salt precipitates calcium pyrophosphate dehydrate and monosodium urate (linked to gout), and protein aggregates associated with inflammatory pathologies such as fibrillar amyloid β (Amβ), can activate inflammasome. These

Induced autophagy enhances inflammasome output

In contrast to the anti-inflammatory effects of basal autophagy, which suppresses unscheduled inflammasome activation [51••, 52••, 53], induced autophagy promotes IL-1β secretion [55••]. This turned out to be related to the fundamental issue of how IL-1β gets secreted outside of the cell. IL-1β is a cytosolic protein without a leader peptide and thus cannot utilize the conventional secretory pathway (export via ER lumen, Golgi, post-Golgi carriers, and their fusion with plasma membrane). It has

Other innate immunity systems and autophagy: IRGM and Gbp

In the context of inflammatory bowel disease, IRGM, a human autophagy factor and a member of the family of immunity-related GTPases (IRG), has been genetically linked with Crohn's disease as a locus of polymorphisms associated with increased risk [9]. IRGM is also a risk locus for tuberculosis in human populations (reviewed in [5]). IRGM is important for physiologically (starvation) pharmacologically (rapamycin), and immunologically (IFN-γ) induced autophagy [8••]. IRGM impacts autophagic

Concluding remarks

Autophagy is intimately intertwined with nearly all aspects of innate immunity, attesting to the contention that immunological functions are one of autophagy's mainstream roles. In this opinion article we have focused on the interrelationship between autophagy and conventional innate immunity systems including TLRs, RLRs, NLRs, and inflammasomes. Additionally, we have ascribed a PRR function to the autophagic adaptors (SLRs), such as p62/sequestosome 1, NBR1, NDP52, and optineurin,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author apologizes to all researchers active in this field for not being able to include all worthy references and in some cases having to resort to referencing reviews instead of primary articles although this was avoided to the maximum extent possible. This work was supported by grants R01 AI069345, RC1AI086845, and R01 AI042999 from National Institutes of Health and a Bill and Melinda Gates Grand Challenge Explorations grant OPP1024376.

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