autophagy in innate recognition of pathogens and adaptive immunity pdf

Autophagy In Innate Recognition Of Pathogens And Adaptive Immunity Pdf

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Jump to navigation. The innate immune system is an evolutionarily conserved system acting as a first-line of defense against invading microbial pathogens and other potential threats to the host.

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Innate Immunity

Autophagy delivers cytoplasmic constituents for lysosomal degradation. Recent studies have demonstrated that this pathway mediates resistance to pathogens and is targeted for immune evasion by viruses and bacteria. Lysosomal degradation products, including pathogenic determinants, are then surveyed by the adaptive immune system to elicit antigen-specific T cell responses. Furthermore, some sources of natural MHC class II ligands display characteristics of autophagy substrates, and autophagosomes fuse with late endosomes, in which MHC class II loading is thought to occur.

Although MHC class II antigen processing via autophagy has so far mainly been described for professional antigen-presenting cells like B cells, macrophages, and dendritic cells, it might be even more important for cells with less endocytic potential, like epithelial cells, when these express MHC class II at sites of inflammation. Therefore, autophagy might contribute to immune surveillance of intracellular pathogens via MHC class II presentation of intracellular pathogen-derived peptides.

Protein degradation in eukaryotic cells is mainly performed by two proteolytic compartments, the catalytic chamber of the proteasome and the lysosome [ 1 , 2 ]. The entry of proteins into proteasomes is highly regulated in order to recycle amino acids only from proteins that have lost their function due to aging or defective ribosomal synthesis defective ribosomal products or DRiPs [ 3 ].

Lysosomal degradation is probably less selective, but shows some degree of specificity by targeting distinct substrates via receptor-mediated endocytosis [ 4 ] or, in the case of long-lived proteins, via autophagy [ 5 ]. These degradation machineries play also pivotal roles during immune responses. In innate immunity, targeting pathogen-derived proteins to proteasomes and lysosomes, leads to their destruction, and a number of phagocytic cells like macrophages utilize lysosomes to degrade extracellular material after internalization.

In addition, activation of the adaptive immune system requires peptide presentation on major histocompatibility complex MHC molecules to T cells [ 6 ]. T cells detect foreign peptides in conjunction with MHC molecules on infected or transformed cells as well as professional antigen-presenting cells APCs. These new studies suggest a role for autophagy in innate and adaptive immunity to intracellular pathogens.

Autophagy, the process of cytoplasmic content degradation via vesicular transport to lysosomes, was originally recognized as a response to starvation [ 7 ] and has been recently confirmed to play an essential role during starvation periods in neonates [ 8 ].

In addition, autophagy is now accepted as the degradation pathway for long-lived proteins and organelles in the steady state [ 9 , 10 ].

Three main pathways of autophagy have been postulated: chaperone-mediated autophagy, microautophagy, and macroautophagy Fig. In chaperone-mediated autophagy, proteins like RNase A get imported into lysosomes via the peptide transporter LAMP-2a [ 11 , 12 ] assisted by cytosolic [ 13 ] and lysosomal [ 14 ] Hsc70 members. Similar to other protein translocation mechanisms across membranes, signal peptides are responsible for the sorting into lysosomes via chaperone-mediated autophagy [ 15 ].

Microautophagy involves the uptake of cytoplasm at the lysosome surface via budding into the lysosome lumen, but this pathway has not been well characterized so far.

Finally, macroautophagy is mediated by the formation of an autophagosome, which then fuses with lysosomes for the degradation of its content [ 16 ]. During autophagosome formation, a double-membrane-coated vesicle is formed via elongation of a cup-shaped isolation membrane, whose origin is poorly defined to date [ 16 ] Fig.

Two ubiquitin-like systems are essential for autophagosome formation. In one of them, the autophagy-related [ 17 ] protein Atg12 is coupled to Atg5 and the resulting complex localizes to the isolation membrane [ 18 ]. The Atg5—Atg12 conjugate is crucial for the elongation of the isolation membrane, and since it preferentially localizes to the concave membrane of the forming autophagosome, it might also determine the curvature of the forming membrane.

The mature autophagosome does not carry Atg5 and Atg Therefore, it is thought that these proteins leave the isolation membrane just prior to or upon closure of the isolation membrane. The second ubiquitin-like system involves coupling of Atg8, also called microtubule-associated protein 1 MAP1 light chain 3 LC3 , to phosphatidylethanolamine in the isolation membrane [ 19 , 20 ].

This essential autophagy protein remains coupled to the autophagosome and is partially degraded with it in lysosomes. Due to its covalent attachment to autophagosomal membranes, GFP-tagged Atg8 is a reliable and specific marker to monitor autophagosomes in vitro [ 21 ] and in vivo [ 10 ]. The mature autophagosome finally fuses with lysosomes, and both its content as well as the inner autophagosomal membrane are degraded. Autophagy delivers cytoplasmic constituents to lysosomes. Three pathways have been described in mammalian cells.

Chaperone-mediated autophagy delivers signal sequence dependent cytosolic proteins directly into the lysosomal lumen a. LAMP-2a, the transporter for chaperone-mediated autophagy, is assisted by cytosolic and lysosomal Hsc70 molecules in this process. Microautophagy involved budding of small substrate containing vesicles into the lysosome for degradation b. Finally, macroautophagy envelopes cell organelles and long-lived proteins with a limiting membrane c.

The resulting autophagosome fuses then with lysosomes for degradation of its content and of the intravesicular membranes. Although no defined signal for substrate selection has been characterized so far, the selective degradation of damaged organelles and long-lived proteins argues that macroautophagy is not entirely nonselective.

Two lines of evidence suggest that protein aggregates might be selected for macroautophagy. Firstly, in the related cytosol-to-vacuole Cvt pathway in yeast, the well-characterized Cvt substrate aminopeptidase I is delivered to the vacuole via double-membrane-coated vesicles after its precursor forms aggregates of dodecamers in the cytosol and binds to Atg19 [ 22 — 24 ].

Secondly, Atg5 gene disruption in mouse embryonic fibroblasts leads to the accumulation of protein aggregates [ 16 ], and the autophagy-linked FYVE protein Alfy localizes partially to autophagosomes and ubiquitin-containing protein aggregates, possibly targeting one to the other [ 25 ]. Although substrate selection for macroautophagy is still an open question, protein aggregates containing long-lived proteins might be selectively incorporated into autophagosomes.

Recently, it was appreciated that macroautophagy not only contributes to the turnover of cytoplasmic constituents, but also targets intracellular pathogens for degradation during innate immunity [ 26 , 27 ]. Bacteria and viruses have developed strategies to escape destruction via macroautophagy, indicating that this is an important mechanism of innate immunity. After phagocytosis, successful microbial pathogens either leave phagosomes for the cytosol before fusion with lysosomes, as is the case for Listeria monocytogenes , or stop their maturation to acidic vesicles, as for Mycobacterium tuberculosis.

Both cytosolic bacteria and endosome-enwrapped pathogens can then be targeted by macroautophagy [ 28 ]. Listeria monocytogenes escapes the phagosome with the help of the protein listeriolysin O and subsequently replicates in the cytosol.

However, when its protein synthesis is inhibited by chloramphenicol, it is trapped by autophagosomes and is delivered for lysosomal destruction [ 29 ]. Similarly, when Streptococcus pyogenes manages to leave endosomes of nonphagocytic cells, it becomes enveloped in autophagosomes and the bacterial load decreases after lysosomal degradation [ 30 ]. Finally, Shigella flexneri lyses its entry phagosome with its gene product IpaB and prevents degradation via macroautophagy with another gene product IcsB [ 31 ].

Mutant bacteria lacking IcsB get targeted by macroautophagic degradation because the Shigella VirG protein binds Atg5 and thereby triggers autophagy. These examples demonstrate that cytosolic bacteria can be degraded via macroautophagy.

Macroautophagic targeting of pathogen-containing phagosomes has been reported for Mycobacterium tuberculosis Mtb. In addition, Legionella pneumophila induced macroautophagy, and bacterial autophagosomes matured faster in infected macrophages from resistant than from susceptible mouse strains, suggesting that rapid clearance of bacterial phagosomes by autophagy correlated with resistance to Legionella infection [ 32 ]. Therefore, both free cytosolic and phagosome-harbored bacteria can be degraded via macroautophagy.

Although several viruses enhance macroautophagy upon infection, its contribution to antiviral innate immunity has been less clearly defined [ 27 ]. Apart from autophagy being one component of the anti-viral type I IFN response, one mammalian homologue of an essential macroautophagy gene in yeast has been implicated in mediating protection against fatal Sindbis-virus-induced encephalitis.

Beclin 1, the mammalian homologue of Atg6, associates with the antiapoptotic factor Bcl-2 to limit Sindbis-virus-induced cell death in the central nervous system [ 34 ]. Apart from this evidence implicating macroautophagy in virus-specific innate immunity, several positive sense RNA viruses have hijacked components of the autophagy machinery for their benefit.

The mouse hepatitis virus, the equine arteritis virus, and the human poliovirus 1 assemble their replication complexes at cytoplasmic double-membrane vesicles, which are reminiscent of autophagosomes [ 35 — 38 ].

Autophagosomes accumulate after infection with these viruses, and stimulation of macroautophagy increases poliovirus yield, whereas inhibition via Atg12 or Atg8 downregulation with RNA interference decreases poliovirus replication [ 39 ]. Another positive sense RNA virus, the pestivirus bovine viral diarrhea virus BVDV , has inserted the atg8 sequence into its genome [ 40 ]. Similarly, Atg8 has to be processed by the Atg4 protease for coupling to autophagosomal membranes, and this proteolytic event could efficiently process NS3 in Atg8-positive BVDV.

Therefore, viruses induce macroautophagy, which mediates innate immunity against some and benefits the life cycle of other viruses. Apart from its role in innate immunity, autophagy might also alarm the adaptive immune system against pathogens that are delivered for lysosomal destruction by autophagy. These peptides of primarily 10—15 amino acids in length are generated by lysosomal degradation. Classically, it was proposed that peptides for MHC class II presentation are primarily generated from endocytosed substrates.

In the following, we will, however, summarize evidence that, in addition, endogenous cytosolic and nuclear antigens can gain access to MHC class II presentation after autophagy. A first indication that a substantial proportion of MHC class II ligands, at least in some cell types, might be generated from intracellular sources came from peptide elution studies [ 41 ].

The two peptides, Atg8 93— and Atg8 93— , lie within the Atg8 sequence, which is specifically attached to phosphatidylethanolamine in autophagosomal membranes and is in part degraded with autophagosomal substrates in lysosomes [ 19 , 20 ].

This finding suggests that components of the autophagy system gain access to MHC class II loading in the steady state. In addition, glyceraldehydephosphate dehydrogenase GAPDH , which has been suggested to be degraded after chaperone-mediated autophagy [ 45 ] and was also found in autophagosomes after macroautophagy [ 46 ], consistently gives rise to natural MHC class II ligands [ 43 , 44 ], but so far, no natural MHC class I ligands have been identified [ 41 ].

Apart from these natural MHC class II ligands eluted from cells in the steady state, HLA-DR-bound peptides have also been analyzed after autophagy induction by serum and amino acid deprivation [ 44 ]. This study indicated that enhanced autophagy leads to increased presentation of cytosolic and nuclear antigens by MHC class II molecules. Furthermore, EBNA1 accumulated in autophagosomes after inhibition of lysosomal acidification, as indicated by monodansylcadaverine staining [ 56 ] and ultrastructural features of EBNA1-containing cytosolic vesicles [ 54 ].

In addition to macroautophagy, chaperone-mediated autophagy has been implicated in endogenous autoantigen processing for MHC class II presentation [ 57 ]. Proteasomal degradation was required for endogenous MHC class II processing of both autoantigens [ 58 , 59 ].

The half-life of proteins might determine in part on which class of MHC molecules an antigen is presented. In addition, defective ribosomal products DRiPs , which are prematurely truncated or malfolded translation products, have in general a short half-life and contribute significantly to MHC class I presentation [ 66 , 67 ].

These studies suggest that short-lived proteins get preferentially presented on MHC class I and long-lived frequently on class II. Short-lived proteins, such as cyclins, DRiPs, and GA domain-deleted EBNA1, have been found to be primarily degraded by proteasomes [ 68 ], whereas long-lived proteins are classical substrates of autophagy [ 5 ].

However, whereas substrate targeting to proteasomes via ubiquitinylation has been characterized in great detail [ 69 ], the selection mechanism of long-lived proteins for autophagy is unclear to date and requires further study in the future. Further evidence for the involvement of macroautophagy in endogenous MHC class II processing comes from cell biological studies.

In particular, the multilamellar MIIC is reminiscent of autophagosomes, which display often multiple delineating membranes [ 71 , 72 ].

Indeed, macroautophagy was recently reported to be required for multilamellar body development in lung epithelial cells [ 73 ]. Inhibition of macroautophagy with 3-methyladenine prevented multilamellar vesicle formation, but did not influence multivesicular, late endosome development. Autophagosomes fuse with late endosomes for the generation of multilamellar vesicles.

Another indication that autophagosomes fuse with MIICs comes from studies that indicate that autophagosomes merge with the endocytic pathway in late endosomes, forming so-called amphisomes [ 74 , 75 ]. In support of amphisomes being fusion vesicles of endosomes and autophagosomes, ultrastructural studies were performed [ 74 , 75 ]. In these studies, colloidal gold-loaded endosomes were found to fuse with double-membrane-enveloped, gold-negative autophagosomes, and these amphisomes could be stabilized via inhibition of lysosomal degradation.

The recent studies on autophagy in endogenous MHC class II antigen processing have focused on classical APCs, like macrophages [ 52 ], dendritic cells [ 53 ], and B cells [ 44 , 51 , 54 , 57 ].

However, this pathway might be even more relevant for cells that express MHC class II in the absence of high endocytic capacity. Interestingly, cortical thymic epithelial cells were found to have high constitutive macroautophagy in mice [ 10 ].

Therefore, cortical thymic epithelial cells might load their MHC class II molecules primarily from intracellular sources and employ in part macroautophagy for the display of nuclear and cytosolic self-proteins. Apart from epithelial cells of the thymus, endothelial and epithelial cells can upregulate MHC class II upon inflammation, and nearly all activated human lymphocytes express MHC class II on their surface [ 78 ].

Especially long-lived pathogen-derived proteins might preferentially enter this pathway and elicit protective immune responses.

This pathway mediates innate immunity to bacteria and viruses and can be triggered by type I and type II interferons. In addition, autophagic degradation links innate with adaptive immunity by delivering antigens for MHC class II presentation.

Autophagy in Innate Recognition of Pathogens and Adaptive Immunity

The cells of this immune system surround and engulf the invader. Non-specific innate immunity The Specific Innate Immunity is where resistance to a particular pathogen is concerned. They are the first to react Helpful? Innate immunity is a general biological principle that provides relevant antimicrobial defense to all types of living beings, including humans Fig. Summary 1: The Innate Immune system is an integrated part Immunity: All mechanisms used by the body to protect itself against all things foreign Immunity: innate or acquired 3. NK cell recognition of infected cells is regulated by a combination of activating and inhibitory receptors.

Being an essential regulatory component of the immune system in these cells, autophagy not only mediates pathogen clearance and cytokine production, but also balances the immune response by preventing harmful overreaction. Interestingly, recent literature indicates that autophagy is positively or negatively regulating the innate immune response in a cell type-specific manner. Moreover, autophagy serves as a bridge between innate and adaptive immunity. It is involved in antigen presentation by delivering pathogen compounds to B and T cells, which is important for effective immune protection. Upon infection, autophagy can also be hijacked by some pathogens for replication or evade host immune responses. As a result, autophagy seems like a double-edged sword to the immune response, strongly depending on the cell types involved and infection models used. A better understanding of this dual potential will help to utilize autophagy in innate immune cells in order to optimize vaccines or treatments against infectious diseases.

Autophagy, autophagy-associated adaptive immune responses and its role in hematologic malignancies

Metrics details. Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes ATG. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors.

Autophagy delivers cytoplasmic constituents for lysosomal degradation. Recent studies have demonstrated that this pathway mediates resistance to pathogens and is targeted for immune evasion by viruses and bacteria. Lysosomal degradation products, including pathogenic determinants, are then surveyed by the adaptive immune system to elicit antigen-specific T cell responses. Furthermore, some sources of natural MHC class II ligands display characteristics of autophagy substrates, and autophagosomes fuse with late endosomes, in which MHC class II loading is thought to occur.

Top PDF Autophagy in Innate Recognition of Pathogens and Adaptive Immunity

Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial , Introducing OncoTarget. Sponsored Conferences. Impact Journals is a member of the Society for Scholarly Publishing. Keywords: autophagy, immune, adaptive immune, cancer immunotherapy, hematologic malignancy.

Show all documents C Atg16L1 regulates endotoxin-induced inflammasome activation. This mechanism may permit pathogens to evade immune re- sponses and perpetuate tolerance to self-antigens in the face of TLR activation by microbes. On the other hand, it has been shown that dectin-1 collaborates with TLR2 in inducing proin- flammatory cytokine secretion in murine macrophages and DCs BDCA-2 has an intra- cellular domain of 21 amino acids without known motifs im- plicated in signal transduction; however, ligation induces Src- family protein-tyrosine kinase-dependent intracellular calcium mobilization and protein-tyrosine phosphorylation of intracel- lular proteins

Autophagy in innate and adaptive immunity against intracellular pathogens

Review ARTICLE

Autophagy is a specialized cellular pathway involved in maintaining homeostasis by degrading long-lived cellular proteins and organelles. Recent studies have demonstrated that autophagy is utilized by immune systems to protect host cells from invading pathogens and regulate uncontrolled immune responses. During pathogen recognition, induction of autophagy by pattern recognition receptors leads to the promotion or inhibition of consequent signaling pathways. Furthermore, autophagy plays a role in the delivery of pathogen signatures in order to promote the recognition thereof by pattern recognition receptors. In this review, we describe the roles of autophagy in innate recognition of pathogens and adaptive immunity, such as antigen presentation, as well as the clinical relevance of autophagy in the treatment of human diseases. Autophagy is a part of cellular system involved in maintaining homeostasis by degrading long-lived cellular constituents. The autophagosome is formed via the elongation of a cup-shaped membrane, and two ubiquitin-like conjugation systems are involved in autophagosome propagation.

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