Autophagy: an emerging immunological paradigm.

Abstract

Autophagy is a fundamental eukaryotic process with multiple cytoplasmic homeostatic roles, recently expanded to include unique stand-alone immunological functions and interactions with nearly all parts of the immune system. In this article, we review this growing repertoire of autophagy roles in innate and adaptive immunity and inflammation. Its unique functions include cell-autonomous elimination of intracellular microbes facilitated by specific receptors. Other intersections of autophagy with immune processes encompass effects on inflammasome activation and secretion of its substrates, including IL-1β, effector and regulatory interactions with TLRs and Nod-like receptors, Ag presentation, naive T cell repertoire selection, and mature T cell development and homeostasis. Genome-wide association studies in human populations strongly implicate autophagy in chronic inflammatory disease and autoimmune disorders. Collectively, the unique features of autophagy as an immunological process and its contributions to other arms of the immune system represent a new immunological paradigm.

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This information is current as
Paradigm
Autophagy: An Emerging Immunological
Vojo Deretic
http://www.jimmunol.org/content/189/1/15
doi: 10.4049/jimmunol.1102108
2012; 189:15-20; ;
J Immunol
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Autophagy: An Emerging Immunological Paradigm
Vojo Deretic
Autophagy is a fundamental eukaryotic process with
multiple cytoplasmic homeostatic roles, recently ex-
panded to include unique stand-alone immunological
functions and interactions with nearly all parts of the
immune system. In this article, we review this growing
repertoire of autophagy roles in innate and adaptive im-
munity and inflammation. Its unique functions include
cell-autonomous elimination of intracellular microbes
facilitated by specific receptors. Other intersections of
autophagy with immune processes encompass effects
on inflammasome activation and secretion of its sub-
strates, including IL-1b, effector and regulatory inter-
actions with TLRs and Nod-like receptors, Ag pre-
sentation, naive T cell repertoire selection, and mature
T cell development and homeostasis. Genome-wide as-
sociation studies in human populations strongly impli-
cate autophagy in chronic inflammatory disease and
autoimmune disorders. Collectively, the unique fea-
tures of autophagy as an immunological process and
its contributions to other arms of the immune sys-
tem represent a new immunological paradigm.
Journal of Immunology, 2012, 189: 15–20.
I
simply autophagy. Autophagy is unique in its capacity to
sequester, remove, or process bulk cytosol, cytoplasmic or-
ganelles (1), invading microbes, and immunological media-
tors (2), as depicted in Fig. 1. Another special property
illustrated in Fig. 1 is that autophagy acts as a topological
inverter—bringing molecules and objects from the cytosolic
side to the luminal side for degradation or processing, inter-
action with luminal receptors, or secretion from cells. In this
review, we discuss the four principal manifestations of im-
munological autophagy (Fig. 1): 1) direct pathogen elimi-
nation assisted by sequestosome 1-like receptors (SLRs); 2)
regulation and effector functions of pattern recognition
The
n this Brief Review, we cover the immunological roles of
macroautophagy (1), a specific autophagic process that
will be referred to herein as sensu stricto autophagy or
receptors (PRRs); 3) regulation of inflammasome activation
and alarmin secretion; and 4) cytoplasmic Ag processing for
MHC II presentation and T cell homeostasis. We relate these
processes to conventional immunological functions, defense
against infectious agents, chronic inflammatory diseases, and
other immunological disorders.
Autophagy pathway
The key morphological features of autophagy are endomem-
branous organelles, called autophagosomes (Fig. 1), whose
formation is controlled by the autophagy-related gene (Atg)
and additional factors comprehensively reviewed elsewhere
(1). Briefly, the Atg system includes Ser/Thr kinases Ulk1 and
Ulk2 (Atg1), Beclin 1 (Atg6; a subunit of the class III PI3K
human vacuolar protein sorting 34 [hVPS34 complexes]),
Atg5–Atg12/Atg16L1 complex, and microtubule-associated
protein L chain 3s (LC3s) (multiple Atg8 orthologs), with
LC3B being a commonly used marker for identification of
autophagosomes (1). Ulk1/2 and Beclin 1-hVPS34 integrate
upstream signals and direct the downstream Atg conjugation
cascade, which involves Atg5–Atg12/Atg16L1 assembly as an
“E3 enzyme” for LC3 lipidation. Lipidated LC3s in con-
junction with other factors assemble, elongate, and close na-
scent autophagic organelles. Autophagosomes interact with
endosomal and lysosomal organelles to mature into autoly-
sosomes (1) or promote unconventional secretion of cyto-
plasmic constituents, as first demonstrated in yeast (3) and
recently shown to include immune mediators (4, 5). In ad-
dition to its immunological functions (2), autophagy plays
a general cellular homeostatic role by supplying nutrients
(e.g., amino acids) through cytosol autodigestion at times
of starvation or growth factor withdrawal, and serves as a
quality and quantity control mechanism for intracellular or-
ganelles (1).
At the transcriptional level, regulation of autophagy is
coupled to the lysosomal system via TFEB (6) and other
proteolytic systems via FoxO3A (7). However, autophagy is
primarily a rapid-response remodeling of membranes that
occurs in the cytoplasm under the control of signaling systems
Department of Molecular Genetics and Microbiology, University of New Mexico
Health Sciences Center, Albuquerque, NM 87131
Received for publication April 17, 2012. Accepted for publication May 2, 2012.
This work was supported by National Institutes of Health Grants AI042999, AI069345,
and ARRA RC1AI086845; Crohn’s & Colitis Foundation of America Grant CCFA2053;
and a Bill and Melinda Gates Grand Challenge Explorations grant.
Address correspondence and reprint requests to Dr. Vojo Deretic, Department of Mo-
lecular Genetics and Microbiology, University of New Mexico Health Sciences Center,
915 Camino de Salud NE, Albuquerque, NM 87131. E-mail address: vderetic@salud.
unm.edu
Abbreviations used in this article: AMPK, AMP-activated protein kinase; Atg,
autophagy-related gene; CD, Crohn’s disease; DAMP, danger/damage-associated mo-
lecular pattern; GWAS, genome-wide association study; HMGB1, high-mobility group
protein B1; hVPS34, human vacuolar protein sorting 34; IKK, inhibitor of NF-kB
kinases; IRGM, immunity-related GTPase M; LC3, microtubule-associated protein L
chain 3; NDP52, nuclear domain 10 protein/Ag nuclear dot 52 kDa protein; NLR,
nucleotide binding and oligomerization domain-like receptor; PAMP, pathogen-
associated molecular pattern; PRR, pattern recognition receptor; RLR, RIG-I–like re-
ceptor; ROS, reactive oxygen species; SLR, sequestosome 1/p6-like receptor; TAK1,
TGF-b–activated kinase 1.
Copyright?2012byTheAmericanAssociationofImmunologists,Inc.0022-1767/12/$16.00
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FIGURE 1.
Invading microbes either escaping the endosomes or phagosome (thin outline) or remaining in phagosomes that can be partially permeabilized (dotted outline) are
captured by galectins and SLRs that recognize tags such as ubiquitin (small red circles) or diacylglycerol and b-galactoside (not shown) on damaged host
membranes. The captured microbes or those cocaptured with the earmarked membranes are delivered into autophagic organelles (thick outline), starting with
phagophores (crescents), progressing through autophagosomes (full white circles), and ending in degradative autolysosomes (full pink circles). SLRs possess an
LC3 interacting region (LIR), phosphorylation sites (black dot, arbitrarily positioned), and a tag recognition domain (UBA, depicted for p62). Galectins (hatched
square), considered to be DAMP receptors, have carbohydrate recognition domains (not shown) that recognize sugars on glycans exposed on the endofacial
lumenal membrane leaflet of permeabilized organelles. (B) Alternatively, autophagy can sequester cytosolic proteins such as ubiquitin and ribosomal proteins
(pear-shaped tan-colored shapes, ribosomes) and digest them into antimicrobial peptides (AMPs) that can be delivered to pathogens confined in phagosomes. (C)
SLRs can engage in proinflammatory signaling via TRAF6 (shown) or atypical PKC (not shown), for example, or promote cell death by activating caspase-8
through aggregation (not shown). (2) PRR regulation and effector functions. (A) Autophagy can be activated downstream of TLR signaling upon recognition of
PAMPs (X’s). (B) As a topological inverter device, autophagy can deliver cytosolic PAMPs to the lumen of endomembranous organelles, where they can interact
with the receptor portions of TLRs. Known functional interactions with NLRs and RLRs are summarized by positive (arrows) and negative (lines symbolizing
inhibition) effects. (3) Inflammasome regulation and secretion of alarmins. Autophagy plays a dual role in controlling inflammasome output: It suppresses basal
levels of inflammasome activation but also assists IL-1b and IL-18 release from the cells via an autophagy-dependent unconventional secretory pathway [(A);
autosecretion]. Inflammasomes, heteromeric protein assemblages (consisting of ASC, caspase 1, and NLRP3 or AIM2) act as platforms for activation in response
to K+efflux or presence and action of DAMPs (silica, crystal-like shape). ROS and mtDNA can be released as endogenous DAMPs by damaged mitochondria if
they are not continuously removed by autophagy. This results in caspase-1 activation and proteolytic processing of proforms of proinflammatory cytokines (IL-
1b). Whereas autophagy lowers the sources of endogenous DAMPs by disposing of depolarized (DCm) or leaky mitochondria (sources of ROS and mtDNA),
autophagy also enables secretion of cytosolic IL-1b (and other alarmins such as HMGB1) during the very early stages of physiological inflammasome activation in
response to exogenous DAMP sources (microbial or sterile). Autosecretion (autophagy-based unconventional secretion; see text for explanations) enables ex-
tracellular release of cytosolic proteins such as IL-1b and HMGB1 per the illustrated process controlled by Atg factors and GRASP (see text). Autosecretion occurs
early in the process of stimulation and is swamped pre- or shortly poststimulation by the anti-inflammatory effects of autophagy. The (Figure legend continues)
The four principal manifestations of immunological autophagy. (1) Direct pathogen elimination assisted by SLRs and DAMP receptors. (A)
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faster than transcriptional changes. The classical nutritional/
energy regulation of autophagy is via mTOR and AMP-
activated protein kinase (AMPK) inhibiting and activating,
respectively, Ulk1/2 (1). This pathway merges with signaling
via the inhibitor of NF-kB kinases (IKK), frequently involved
in immune signaling. IKKa and IKKb transduce the classical
signal for autophagy induction—starvation (8)—but this sig-
naling is not based on nuclear NF-kB responses. Instead, IKK
and AMPK signaling merge via TGF-b–activated kinase 1
(TAK1) and its activators TAB2 and TAB3. Upon autophagy
induction, TAB2 and TAB3 dissociate from and thus activate
Beclin 1 and also bind to and activate TAK1 (8), whereas
TAK1 in turn phosphorylates and activates AMPK.
In T cells, autophagy is activated upon TCR engagement
and CD28 costimulation and supports their effector func-
tions and proliferation (9). Recently, class III PI3K hVPS34
was found to be dispensable for autophagy induction in
T cells, albeit required for T cell homeostasis via its regula-
tion of receptor endocytosis (10), bringing up the possibility
of alternative pathways in PI3P signaling, as suggested by the
positive role of class I PI3K p110b (11).
Innate immune signaling can induce autophagy. TRAF6
downstream of TLR4 activates autophagy (12). Alarmins or
damage-associated molecular patterns (DAMPs) induce auto-
phagy (13, 14). High-mobility group protein B1 (HMGB1),
an alarmin, undergoes translocation from the nucleus into the
cytoplasm and then out of the cells by unconventional se-
cretion (5, 15) or cell death-associated release, inducing auto-
phagy at each stage: cytoplasmic through de-repression
of Beclin 1 by displacing its negative regulator Bcl-2, or ex-
tracellularly via RAGE signaling (13, 14). In addition to
HMGB1, DAMPs such as ATP, IL-1b, and DNA com-
plexes are known to induce autophagy (reviewed in Ref.
16).
Autophagy in direct pathogen elimination
From an evolutionary perspective, the most primal manifes-
tation of immunological autophagy is direct capture and
degradation of invading intracellular microbes by autophagy
(Fig. 1, panel 1, left). This cell-autonomous defense function
of autophagy is often countered by microbial adaptation
mechanisms, and a number of highly adapted pathogens can
convert autophagic organelles into growth-supporting com-
partments (17). Autophagic capture of intracellular microbes
is facilitated by autophagic adaptors, referred to as seques-
tosome 1/p62-like receptors (SLRs) (18). SLRs have LC3
interacting regions and cargo-tag (e.g., ubiquitin) recognition
domains and are modulated by protein kinases. Salmonella
requires multiple SLRs [p62, nuclear domain 10 protein/Ag
nuclear dot 52 kDa protein (NDP52), optineurin] (19, 20),
phosphorylation of at least one of the SLRs (optineurin) with
an IKK-related kinase, TBK-1 (20), and an intracellular
DAMP receptor (galectin 8) (21). The SLRs p62 and NDP52
are also engaged in clearance of Shigella and Listeria (22–24),
whereas streptococci are affected by NDP52 (19). Sindbis
virus interacts with p62 (25). Candidate E3 ligases contrib-
uting to target ubiquitination have been identified in some
instances: SMURF1 for sindbis virus (26) and LRSAM1 as
a candidate for Salmonella (27).
The most recent player in these processes is galectin 8, a
cytosolic lectin binding to b-galactoside glycans. The mem-
brane glycans are normally present only on the luminal side of
parasitophorous vacuoles. However, upon membrane damage
the glycans come in contact with the cytosol and thus become
recognized by cytosolic galectins (21) (Fig. 1, panel 1, hatched
square). Galectin 8 is important in restricting Salmonella
proliferation, and plays an early role until supplanted by a
phase dominated with ubiquitin and ubiquitin-recognizing
SLR—NDP52. It appears that the phases and the sequence
of recognizing membrane damage could be ushered in by the
appearance of diacylglycerol (28), followed by galectin-b–
galactoside recognition, followed by NDP52–ubiquitin rec-
ognition. Because galectin 8 and NDP52 interact, a sequential
action is doubly ensured. Galectin 8 is important for the re-
cruitment of NDP52, as the requirement for galectin 8 to
restrict Salmonella proliferation could be bypassed by ex-
pressing a fusion hybrid between galectin 3 and NDP52.
Galectin 3 per se is not required for restriction, although it is
found on Salmonella vacuoles, primarily because it, unlike
galectin 8, cannot interact with NDP52. Galectin 8 recog-
nizes host membrane glycans and, indirectly, Salmonella car-
bohydrates, albeit it can directly recognize blood group B-
positive E. coli O86. Galectin 8 is also important for Shi-
gella and Listeria, and can even detect sterile damage to en-
dosomes and lysosomes.
SLRs can also act in a completely different manner to
promote autophagic killing of intracellular microbes (Fig. 1,
panel 1, right). They gather cytoplasmic proteins (e.g., ubiq-
uitin and ribosomal proteins) to be converted in autolyso-
somes into antimicrobial products that, upon delivery to cy-
toplasmic compartments harboring microbes, transform them
into autophagolysosomes, organelles with enhanced antimi-
crobial capacities relative to conventional phagolysosomes
(29–31).
Autophagy and pattern recognition receptors
Autophagy interacts with classical PRRs, including TLRs,
Nod-like receptors (NLRs), and RIG-I–like receptors (RLRs).
TLRs and autophagy intersect in two ways, illustrated in Fig.
1, panel 2. First, autophagy is an effector mechanism (e.g.,
elimination of microbes illustrated in Fig. 1, panel 1) down-
stream of TLR activation. TLR4 triggers autophagy via
TRAF6 E3 ligase, ubiquitination of Beclin 1, and Bcl-2 dis-
sociation from the BH3 domain of Beclin 1 (12). Second,
autophagy as a topological inverter device can bring cytosolic
pathogen-associated molecular pattern (PAMP) molecules
into the lumen, where they can bind the ligand recognition
side of the TLR. This has been demonstrated for TLR7 (32),
TLR4 ligands (33), and TLR9 in the context of BCR sig-
naling (34).
latter keep the tonic levels of inflammasome activation low and bring them back to resting levels following stimulation. (4) Cytosolic Ag processing for Ag
presentation. Autophagy assists as a topological inversion device in delivery of cytosolic (and nuclear) proteins to MHC II processing and presentation com-
partments. Explanations in the text include relationships to selection of naive T cell repertoires and citrullination of Ags. AP, Autophagy; mtDNA, mitochondrial
DNA; ROS, reactive oxygen species.
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NLR and autophagy interactions are evolutionarily con-
served from Drosophila (35) to humans (16). Nod1 and Nod2
interact with Atg16L1 (36, 37), of significance for Crohn’s
disease (CD) because Nod2 and Atg16L1 are risk loci for CD
(38). NLRC4 (Ipaf) and NLRP4 inhibit autophagy (39) and
are found in macromolecular complexes with Beclin 1. RLRs
activate autophagy with biologically important effects (40),
but thus far, more attention has been given to negative reg-
ulation of RLR signaling by autophagy factors Atg5–Atg12
(41) and Atg9 (42). Atg9 negatively regulates trafficking and
activation of TBK-1 in the type I IFN response to dsDNA
(42).
Autophagy and inflammasomes
Autophagy and inflammasomes interact in two ways (Fig. 1,
panel 3). All reports thus far (5, 43–46) agree on the obser-
vation that autophagy plays a negative role in inflammasome
activation. Autophagy lowers the basal level of inflammasome
activation by continually removing endogenous irritants (43,
44). For example, autophagy prevents spurious inflammasome
activation by eliminating defunct mitochondria that otherwise
represent endogenous sources of inflammasome agonists, such
as reactive oxygen species (ROS) and mitochondrial DNA
(43, 44) (Fig. 1, panel 3). In the absence of basal autophagy,
endogenous factors lead to inflammasome activation and in-
creased IL-1b processing and represent sources of sterile in-
flammation. This explains how loss of Atg16L1 elevates IL-1b
levels in a murine model of CD (47).
On the flip side, autophagy plays a positive (but only acute,
short-term) role in delivering outside the cell the effector
products of inflammasome activation, such as IL-1b and
potentially other alarmins, in a process referred to as the
unconventional secretion of IL-1b (5). Although IL-1b and
IL-18 do not have signal peptides to deliver them into the
lumen of the organelles of the conventional secretory pathway
(ER–Golgi–plasma membrane), they are released extracellu-
larly upon inflammasome activation. This is, at least in part,
supported by the topological inversion properties of auto-
phagy, ferrying molecules from the cytosolic side into the
lumen of putative secretory vesicles. However, this effect
wanes quickly with time, and the downregulation of inflam-
masomes by autophagy becomes dominant once again (46).
Thus, autophagy negatively controls inflammasome activation
(5, 43–46) and positively controls IL-1b secretion per se (5).
The topological inversion action and the positive role of
autophagy in secretion of alarmins are not limited to IL-1b
and extend to HMGB1 (5).
Autophagy in Ag presentation and T cell homeostasis
The role of autophagy as a topological inverter (transport from
cytosol to lumen) and its other functions contribute to MHC
II presentation of endogenous cytosolic Ags (33, 48, 49) (Fig.
1, panel 4). The physiological role of this is manifested in
immune surveillance of viral infections (48) and inhibition of
this process by HIV-1 (49). Autophagy-dependent presenta-
tion of endogenous Ags plays a part in positive and negative
selection of naive T cell repertoires in the thymus (50). It has
been hypothesized that peripheral tissue autophagic activities
may have to be matched by central tolerance mechanisms
dependent on autophagy in the thymus to prevent autoim-
munity (50). Autophagy functions in mature T cell homeo-
stasis, and is essential for T cell survival following exit from
the thymus, in part based on the requirement for autophagy
to physiologically reduce the mitochondrial and ER content
in maturing T cells (51–53).
Autophagy in chronic inflammatory and autoimmune diseases
Genetic links between autophagy and chronic inflammatory
disorders and autoimmune diseases continue to be uncovered
by genome-wide association studies (GWAS). Genetic varia-
tions in the PRDM1–ATG5 intergenic region have been as-
sociated with rheumatoid arthritis (54). Autophagy specifi-
cally favors presentation of citrullinated proteins, which may
contribute to autoimmune disorders such as rheumatoid ar-
thritis (55). The initial GWAS linking of ATG16L1 and
IRGM [immunity-related GTPase M; a modulator of auto-
phagy (56, 57)] with CD (38) has been replicated in nearly 50
independent population studies. Polymorphisms in another
autophagy gene, ULK1, are also associated with CD (58).
Genetic associations of CD with IRGM have been extended
to IRGM copy number variants in human populations (59).
IRGM has further been linked to systemic lupus eryth-
ematosus in a recent meta-analysis of autoimmune diseases
(60). GWAS in different populations link ATG5 variants to
systemic lupus erythematosus (61, 62). This genetic evidence
and other studies implicate autophagy in chronic inflamma-
tory diseases and autoimmune disorders.
Conclusions
The initialsporadic observations thatautophagy canplay arole
in cell-autonomous defense against intracellular bacteria such
as Mycobacterium tuberculosis (63) and streptococci (64) have
been extended in the past several years to various facets of
immunity. The connections of autophagy with the normal
function of innate and adaptive immunity at almost every
level, the genetic and functional associations with immuno-
logical disorders, and the unique, specialized mechanisms of
autophagy as stand-alone immune processes presented in this
article and elsewhere (2) are consistent with the thesis of this
review that autophagy represents a new and growing immu-
nological paradigm.
Acknowledgments
I apologize to colleagues for omissions imposed by space limitations, including
microbial defenses against autophagy, nonautophagic functions of the ATG
factors, and roles of autophagy processes other than macroautophagy. I thank
Carolyn Mold for comments on the text and Dara Elerath for graphic design.
Disclosures
The author has no financial conflicts of interest.
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