The nucleotidyl transferase cGAS, its second-messenger product cGAMP, and the cGAMP sensor STING form the basic mechanism of DNA sensing in the cytoplasm of mammalian cells. Several new reports now ...uncover key structural features associated with DNA recognition by cGAS and the catalytic mechanisms of cGAMP generation. Concurrent studies also reveal unique phosphodiester linkages in endogenous cGAMP that distinguish it from microbial cGAMP and other cyclic dinucleotides. Together, these studies provide a new perspective on DNA recognition in the innate immune system.
Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we ...found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3−/− mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.
•NLRC3 reduces IFN-I induced by intracellular DNA, HSV-1, and c-di-GMP•NLRC3 directly associates with STING and can block STING trafficking to puncta•NLRC3 also associates with TBK1 and interferes with STING-TBK1 interaction•Nlrc3−/− mice are more resistant to HSV-1 infection and exhibit elevated cytokines
Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the “sepsis syndrome,” a widespread and uncontrolled inflammatory response. Though it is well ...recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection.
Display omitted
► TRIF is essential for NLRP3 inflammasome activation by EHEC and C. rodentium ► TRIF signaling via type I interferon couples caspase-11 induction and autoactivation ► The TRIF-IFN-caspase-11 axis licenses NLRP3 inflammasome activation ► Caspase-11 activation licenses NLRP3 activation by Gram-negative, but not -positive, bacteria
TRIF is as an integral component of NLRP3 inflammasome activation during Gram-negative bacterial infection, highlighting the central role of TLRs as master regulators of the NLRP3 inflammasome and providing new targets for therapeutic intervention in septic shock.
Highlights • New inflammasomes and new microbial triggers of inflammasomes have been identified. • Cytosolic LPS is detected by caspase-11 resulting in its activation. • A novel pyrin inflammasome ...responds to pathogen-induced modifications of host proteins. • Identification of a new NLRP6 pathway controlling mucus production.
Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat ...containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.
Display omitted
•Infection-associated ER stress initiates mitochondrial damage through IRE1α•Mitochondrial damage is required for IRE1α-dependent IL-1β production•IRE1α promotes mitochondrial damage via NLRP3, caspase-2, and Bid•The NLRP3-caspase-2 axis drives general ER stress-induced inflammasome activation
The endoplasmic reticulum stress response modulates inflammatory responses during chemical stress or microbial infection. O’Riordan and colleagues report that endoplasmic reticulum stress sensor IRE1α induces ROS-dependent NLRP3 translocation to mitochondria. NLRP3 stimulates the caspase-2-Bid mitochondrial damage pathway, leading to release of mitochondrial danger signals that activate the inflammasome.
Germline-encoded pattern recognition receptors (PRRs) sense microbial or endogenous products released from damaged or dying cells and trigger innate immunity. In most cases, sensing of these signals ...is coupled to signal transduction pathways that lead to transcription of immune response genes that combat infection or lead to cell death. Members of the NOD-like receptor (NLR) family assemble into large multiprotein complexes, termed inflammasomes. Inflammasomes do not regulate transcription of immune response genes, but activate caspase-1, a proteolytic enzyme that cleaves and activates the secreted cytokines interleukin-1β and interleukin-18. Inflammasomes also regulate pyroptosis, a caspase-1-dependent form of cell death that is highly inflammatory. Here, we review exciting recent developments on the role of inflammasome complexes in host defense and the discovery of a new DNA sensing inflammasome, and describe important progress made in our understanding of how inflammasomes are activated. Additionally, we highlight how dysregulation of inflammasomes contributes to human disease.
The innate immune system represents the first line of defense during infection and is initiated by the detection of conserved microbial products by germline‐encoded pattern recognition receptors ...(PRRs). Sensing through PRRs induces broad transcriptional changes that elicit powerful inflammatory responses. Tight regulation of these processes depends on multiple regulatory checkpoints, including noncoding RNA species such as microRNAs. In addition, long noncoding RNAs (lncRNAs) have recently gained attention as important regulators of gene expression acting through versatile interactions with DNA, RNA, or proteins. As such, these RNAs have a multitude of mechanisms to modulate gene expression. Here, we summarize recent advances in this rapidly moving and evolving field. We highlight the contribution of lncRNAs to both the development and activation of innate immune cells, whether it is in the nucleus, where lncRNAs alter the transcription of target genes through interaction with transcription factors, chromatin‐modifying complexes or heterogenous ribonucleoprotein complexes, or in the cytosol where they can control the stability of target mRNAs. In addition, we discuss experimental approaches required to comprehensively investigate the function of a candidate noncoding RNA locus, including loss‐of‐function approaches encompassing genomic deletions, RNA interference, locked nucleic acids, and various adaptions of the CRISPR/Cas9 technology.
Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression, acting through versatile interactions with DNA, RNA, or proteins. We highlight how lncRNAs contribute to the development and activation of immune cells. We also discuss experimental approaches to investigate the function of a candidate noncoding RNA locus.
Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is ...currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the
effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome-dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.
Succination inactivates gasdermin D and blocks pyroptosis Humphries, Fiachra; Shmuel-Galia, Liraz; Ketelut-Carneiro, Natalia ...
Science (American Association for the Advancement of Science),
09/2020, Letnik:
369, Številka:
6511
Journal Article
Recenzirano
Odprti dostop
Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by ...defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
Innate immune responses combat infectious microorganisms by inducing inflammatory responses, antimicrobial pathways and adaptive immunity. Multiple genes within each of these functional categories ...are coordinately and temporally regulated in response to distinct external stimuli. The substantial potential of these responses to drive pathological inflammation and tissue damage highlights the need for rigorous control of these responses. Although transcriptional control of inflammatory gene expression has been studied extensively, the importance of post-transcriptional regulation of these processes is less well defined. In this Review, we discuss the regulatory mechanisms that occur at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and that have instrumental roles in controlling both the magnitude and duration of the inflammatory response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
