SUMMARY 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 pyrindomain (PYD) interactions between sensors and ASC, and 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 cryo-EM 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.

An inducible program of inflammatory gene expression is central to anti-microbial defenses. Signal-dependent activation of transcription factors, transcriptional co-regulators and chromatin modifying factors collaborate to control this response. Here we identify a long noncoding RNA that acts as a key regulator of this inflammatory response. Germline-encoded receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2 mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad acting regulatory component of the circuit that controls the inflammatory response.

SUMMARY Long intergenic noncoding RNAs (lincRNA) are important regulators of gene expression. Although lincRNAs are expressed in immune cells, their functions in immunity are largely unexplored. Here we identify an immunoregulatory lincRNA, lincRNA-EPS, that is precisely regulated in macrophages to control the expression of immune response genes (IRGs). Transcriptome analysis of macrophages from lincRNA-EPS-deficient mice, combined with gain-of-function and rescue experiments, revealed a specific role for this lincRNA in restraining IRG expression. Consistently, lincRNA-EPS-deficient mice manifest enhanced inflammation and lethality following endotoxin challenge in vivo. lincRNA-EPS associates with chromatin at regulatory regions of IRGs to control nucleosome positioning and repress transcription. Further, lincRNA-EPS mediates these effects by interacting with heterogeneous nuclear ribonucleoprotein L via a CANACA motif located in its 3′ end. Together, these findings identify lincRNA-EPS as a repressor of inflammatory responses highlighting the importance of lincRNAs in the immune system.

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

All cells of the immune system rely on a highly integrated and dynamic gene expression program that is controlled by both transcriptional and post-transcriptional mechanisms. Recently, non-coding RNAs, including long non-coding RNAs (lncRNA), have emerged as important regulators of gene expression in diverse biological contexts. Long non-coding RNAs control gene expression in the nucleus by modulating transcription or via post-transcriptional mechanisms targeting the splicing, stability or translation of mRNAs. Our knowledge of lncRNA biogenesis, their cell-type specific expressions, and their versatile molecular functions are rapidly progressing in all areas of biology. Here we discuss these exciting new regulators and highlight an emerging paradigm of lncRNA-mediated control of gene expression in the immune system.

Background: IFI16 binds dsDNA and elicits a type I interferon response. Results: IFI16 knockdown cells show a decrease in interferon production and ISG expression in response to DNA and RNA ligands and cyclic dinucleotides. Conclusion: IFI16 transcriptionally regulates ISGs to enhance IFN responses to multiple IFN-inducing ligands.Significance: IFI16 has a broader role in the regulation of ISG expression.

Natural antisense transcripts (NATs) are a class of long noncoding RNAs (lncRNAs) that are complementary to other protein-coding genes. Although thousands of NATs are encoded by mammalian genomes, their functions in innate immunity are unknown. Here, we identify and characterize a novel NAT, AS-IL1α that is partially complementary to IL-1α. Similar to IL-1α, AS-IL1α is expressed at low levels in resting macrophages and is induced following infection with Listeria monocytogenes or stimulation with TLR ligands (Pam3CSK4, LPS, PolyI:C). Inducible expression of IL-1α mRNA and protein were significantly reduced in macrophages expressing shRNA that target AS-IL1α. AS-IL1α was located in the nucleus and did not alter the stability of IL-1α mRNA. Instead, AS-IL1α was required for the recruitment of RNA Polymerase II (RNAPII) to the IL-1α promoter. In summary, our studies identify AS-IL1α as important regulator of IL-1α transcription during the innate immune response.

Recognition of microbial nucleic acids is one strategy by which mammalian hosts respond to infectious agents. Intracellular DNA which is introduced into cells during infection elicits potent inflammatory responses by triggering the induction of antiviral type I interferons and the maturation and secretion of inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin (IL)-1β and IL-18. In addition, if nucleases such as DNase II or DNase III (Trex1) fail to clear self-DNA accumulated DNA gains access to intracellular compartments where it drives inflammatory responses leading to autoimmune disease. In this review, we discuss a rapidly evolving view of how cytosolic DNA sensing machineries coordinate antimicrobial immunity and if unchecked lead to autoimmune disease.