An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome

Bürckstümmer, Tilmann; Baumann, Christoph; Blüml, Stephan; Dixit, Evelyn; Dürnberger, Gerhard; Jahn, Henriette; Planyavsky, Melanie; Bilban, Martin; Colinge, Jacques; Bennett, Keiryn L.; Superti‐Furga, Giulio

doi:10.1038/ni.1702

Cited by 952 publications

(778 citation statements)

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“…IL-1b secretion is governed by the DNA sensor AIM2 that has recently been identified [11][12][13][14]. IFN-b production is regulated by the DNA-dependent activator of IFN-regulatory factors (DAI, formerly known as DLM-1/ZBP1) [15] and as-yet unknown DNA sensors [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Despite ''thousands of man-years worth of DNA transfections'', it has only recently been noticed that introduction of dsDNA into the cytosol triggers a potent innate immune response, leading to the production of IL-1b, IFN-b and other cytokines [8][9][10]. IL-1b secretion is governed by the DNA sensor AIM2 that has recently been identified [11][12][13][14]. IFN-b production is regulated by the DNA-dependent activator of IFN-regulatory factors (DAI, formerly known as DLM-1/ZBP1) [15] and as-yet unknown DNA sensors [16,17].…”

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The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

et al. 2009

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Recognition of foreign DNA by cytosolic innate immune receptors triggers the production of IFN-b. However, it is unclear whether different types of DNA ligands are recognized by similar receptors and whether the resulting response is distinct from the endosomal TLR response. To address these questions, we compared the two most commonly used types of DNA ligands (IFN-stimulatory DNA (ISD) and poly(dAdT)) and assessed the minimal structural requirements for stimulatory capacity in RAW264.7 cells. Gene expression signatures and competition experiments suggest that ISD and poly(dAdT) are qualitatively indistinguishable and differ from the CpG-containing oligonucleotides triggering the TLR9 pathway. Structure -activity relationship analyses revealed that a minimal length of two helical turns is sufficient for ISD-mediated IFN-b induction, while phosphorylation at the 5 0 -end is dispensable. Altogether, our data suggest that, in murine macrophages, only one major cytosolic DNA recognition pathway is operational. IntroductionInnate immunity represents the first line of defense against invading pathogens. PRR recognize molecular features that are conserved among many pathogens, so called PAMP. PRR are localized on the plasma membrane, the endosome or the cytosol and belong to distinct classes, most notably the TLR, the NOD-like receptors and the RIG-I-like helicases (RLH) [1,2]. Engagement of PRR by specific ligands triggers intracellular signaling cascades that culminate in the production and secretion of type-I IFN, cytokines and chemokines.An invading virus can either be sensed by endosomal TLR (TLR3, 7/8 or 9) or by cytosolic RLH [3], whereas, TLR3 and TLR7/8 recognize viral RNA, TLR9 senses the presence of viral DNA containing CpG motifs [4]. The RLH detect viral RNA in the cytosol [5]. This raises the question of how the host cell Eur. J. Immunol. 2009. 39: 1929-1936 DOI 10.1002 Innate immunity 1929distinguishes between viral and cellular RNA that are simultaneously present in the same subcellular compartment. It has recently been shown that many viral RNA, unlike cellular RNA, contain a triphosphate moiety at the 5 0 -end, which is recognized by RIG-I, the founding member of the RLH family [6,7]. Despite ''thousands of man-years worth of DNA transfections'', it has only recently been noticed that introduction of dsDNA into the cytosol triggers a potent innate immune response, leading to the production of IL-1b, IFN-b and other cytokines [8][9][10]. IL-1b secretion is governed by the DNA sensor AIM2 that has recently been identified [11][12][13][14]. IFN-b production is regulated by the DNA-dependent activator of IFN-regulatory factors (DAI, formerly known as DLM-1/ZBP1) [15] and as-yet unknown DNA sensors [16,17]. With regard to the IFN pathway, it has been suggested that the B-conformation of DNA is stimulatory, whereas Z-DNA is not [9]. Another report suggests that the exchange of the phosphate backbone for a phosphorothioate backbone renders the DNA inert, implying that the DNA backbone is the site of recog...

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The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

et al. 2009

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“…In recent years, the cell line has also been used extensively in proteomics experiments including a large‐scale proteome 10, phagosome proteomics 4, 8, 11, responses to cytokines 12, 13, and identification of DNA receptors 14.…”

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High‐resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow derived macrophages

et al. 2015

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Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in‐depth proteomics characterization of phagosomes from RAW 264.7 and bone marrow derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicate that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec‐1. Moreover, bone marrow derived macrophages phagosomes mature considerably faster by fusion with endosomes and the lysosome which we validated using fluorogenic phagocytic assays. We provide a valuable resource for researcher in the field and recommend careful use of the RAW 264.7 cell line when studying phagosome functions. All MS data have been deposited in the ProteomeXchange with identifier PXD001293 (http://proteomecentral.proteomexchange.org/dataset/PXD001293).

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“…A major breakthrough in this regard was the purification in 2002 by Tschopp and colleagues of the inflammasome [2], a large multiprotein complex that assembles in cells and leads to the activation of the proteolytic enzyme caspase-1. To date, four inflammasome complexes have been partially characterized, containing NLRP1 [3], NLRP3 [4], IPAF/NLRC4 [5] or AIM2 [6][7][8][9] (Fig. 1).…”

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“…While a direct ligand-receptor interaction has been shown for activation of the AIM2 inflammasome by cytosolic dsDNA [6,7,9], such a mechanism is unlikely for NLRP3 in light of the diverse physico-chemical nature of its activating stimuli. There are divergent opinions regarding this matter and a number of models have been proposed.…”

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NLR‐containing inflammasomes: Central mediators of host defense and inflammation

Fitzgerald

2010

Eur J Immunol

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An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome

Cited by 952 publications

References 26 publications

The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

High‐resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow derived macrophages

NLR‐containing inflammasomes: Central mediators of host defense and inflammation

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