The detection of pathogens through nucleic acid sensors is a defining principle of innate immunity. RNA-sensing and DNA-sensing receptors sample subcellular compartments for foreign nucleic acids ...and, upon recognition, trigger immune signalling pathways for host defence. Over the past decade, our understanding of how the recognition of nucleic acids is coupled to immune gene expression has advanced considerably, particularly for the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signalling effector stimulator of interferon genes (STING), as well as the molecular components and regulation of this pathway. Moreover, the ability of self-DNA to engage cGAS has emerged as an important mechanism fuelling the development of inflammation and implicating the cGAS-STING pathway in human inflammatory diseases and cancer. This detailed mechanistic and biological understanding is paving the way for the development and clinical application of pharmacological agonists and antagonists in the treatment of chronic inflammation and cancer.
The gasdermins are a family of pore-forming proteins recently implicated in the immune response. One of these proteins, gasdermin D (GSDMD), has been identified as the executioner of pyroptosis, an ...inflammatory form of lytic cell death that is induced upon formation of caspase-1-activating inflammasomes. The related proteins GSDME and GSDMA have also been implicated in autoimmune diseases and certain cancers. Most gasdermin proteins are believed to have pore-forming capabilities. The best-studied member, GSDMD, controls the release of the proinflammatory cytokines IL-1ß and IL-18 and pyroptotic cell death. Because of its potential as a driver of inflammation in septic shock and autoimmune diseases, GSDMD represents an attractive drug target. In this review, we discuss the gasdermin proteins with particular emphasis on GSDMD and its mechanism of action and biological significance.
The study of innate immunity and its link to inflammation and host defense encompasses diverse areas of biology, ranging from genetics and biophysics to signal transduction and physiology. Central to ...our understanding of these events are the Toll-like receptors (TLRs), an evolutionarily ancient family of pattern recognition receptors. Herein, we describe the mechanisms and consequences of TLR-mediated signal transduction with a focus on themes identified in the TLR pathways that also explain the operation of other immune signaling pathways. These themes include the detection of conserved microbial structures to identify infectious agents and the use of supramolecular organizing centers (SMOCs) as signaling organelles that ensure digital cellular responses. Further themes include mechanisms of inducible gene expression, the coordination of gene regulation and metabolism, and the influence of these activities on adaptive immunity. Studies in these areas have informed the development of next-generation therapeutics, thus ensuring a bright future for research in this area.
Kagan and Fitzgerald comprehensively review the functions and mechanisms of Toll-like receptors (TLRs), which are crucial detectors of microbial biomolecules and mediators of cellular immunity. They synthesize the overarching themes that have emerged from TLR signaling but are repeated throughout the pattern recognition receptor (PRR) superfamily.
Canonical activation of the inflammasome is critical to promote caspase-1-dependent maturation of the proinflammatory cytokines IL-1β and IL-18, as well as to induce pyroptotic cell death in response ...to pathogens and endogenous danger signals. Recent discoveries, however, are beginning to unveil new components of the inflammasome machinery as well as the full spectrum of inflammasome functions, extending their influence beyond canonical functions to regulation of eicosanoid storm, autophagy, and metabolism. In addition, the receptor components of the inflammasome can also regulate diverse biological processes, such as cellular proliferation, gene transcription, and tumorigenesis, all of which are independent of their inflammasome complex-forming capabilities. Here, we review these recent advances that are shaping our understanding of the complex biology of the inflammasome and its constituents.
Recent discoveries are helping to unveil the complexity of the inflammasome’s biology, extending its function beyond the traditional roles in cytokine maturation and cell death to a variety of non-canonical functions, such as regulation of autophagy, metabolism, gene expression, cellular proliferation, and tumorigenesis.
Immunobiology of Long Noncoding RNAs Atianand, Maninjay K; Caffrey, Daniel R; Fitzgerald, Katherine A
Annual review of immunology,
04/2017, Volume:
35, Issue:
1
Journal Article
Peer reviewed
Open access
The discovery of long noncoding RNAs (lncRNA) has provided a new perspective on gene regulation in diverse biological contexts. lncRNAs are remarkably versatile molecules that interact with RNA, DNA, ...or proteins to promote or restrain the expression of protein-coding genes. Activation of immune cells is associated with dynamic changes in expression of genes, the products of which combat infectious microorganisms, initiate repair, and resolve inflammatory responses in cells and tissues. Recent evidence indicates that lncRNAs play important roles in directing the development of diverse immune cells and controlling the dynamic transcriptional programs that are a hallmark of immune cell activation. The importance of these molecules is underscored by their newly recognized roles in inflammatory diseases. In this review, we discuss the contribution of lncRNAs in the development and activation of immune cells and their roles in immune-related diseases. We also discuss challenges faced in identifying biological functions for this large and complex class of genes.
Display omitted
•Apoptosis, pyroptosis and necroptosis are programmed cell death pathways.•Pyroptosis share many features with apoptosis and necroptosis.•Discovery of small molecules that targets ...cell death is an interesting new strategy to treat inflammatory disease.
Cell death is an essential process in all living organisms and occurs through different mechanisms. The three main types of programmed cell death are apoptosis, pyroptosis, and necroptosis, and each of these pathways employs complex molecular and cellular mechanisms. Although there are mechanisms and outcomes specific to each pathway, they share common components and features. In this review, we discuss recent discoveries in these three best understood modes of cell death, highlighting their singularities, and examining the intriguing notion that common players shape different individual pathways in this highly interconnected and coordinated cell death system. Understanding the similarities and differences of these cell death processes is crucial to enable targeted strategies to manipulate these pathways for therapeutic benefit.
Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses ...remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8+ T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
Display omitted
•Spontaneous T cell responses against tumors require the host STING pathway in vivo•Tumor-derived DNA can induce type I interferon production via STING•Tumor DNA can be identified in host APCs in the tumor microenvironment in vivo
The tumor-derived factors and host innate immune pathways that activate T cell responses against cancer are unclear. Gajewski and colleagues show a requirement for STING-dependent cytosolic DNA sensing in this process, via a mechanism associated with acquisition of tumor cell DNA by antigen-presenting cells.
Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in ...melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
Display omitted
► Electrostatic attraction underlies innate dsDNA recognition by the HIN domains ► Both OB folds and the linker between them engage the dsDNA backbone ► An autoinhibited state of AIM2 is activated by DNA that liberates the PYD domain ► DNA serves as an oligomerization platform for the inflammasome assembly
Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of ...inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASCPYD filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization.
Display omitted
Display omitted
•AIM2 and NLRP3 inflammasomes are filamentous assemblies in vitro and in cells•3.8 Å cryo-EM structure of ASCPYD depicts the underlying oligomerization mechanism•Fluorescence polarization assays suggest nucleation-induced filament formation•ASC-dependent inflammasomes use a polymerization mechanism for caspase-1 activation
Extremely high-resolution cryoelectron microscopy analysis of inflammasomes establishes that assembly of these complexes, which are integral to the innate immune response to pathogens, requires two successive steps of nucleation-induced polymerization to bring inflammasome sensor proteins together and to activate downstream signaling events.
Highlights • The expression of lncRNAs in the immune system is cell type- and context-dependent. • Several lncRNAs identified to date regulate immune gene expression. • LncRNAs play crucial role in ...host–pathogen interactions. • The majority of disease-associated SNPs lie in regulatory regions of the genome.
PDF
