The gasdermins are a family of recently identified pore-forming effector proteins that cause membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. Gasdermins contain ...a cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. Proteolytic cleavage between these two domains releases the intramolecular inhibition on the cytotoxic domain, allowing it to insert into cell membranes and form large oligomeric pores, which disrupts ion homeostasis and induces cell death. Gasdermin-induced pyroptosis plays a prominent role in many hereditary diseases and (auto)inflammatory disorders as well as in cancer. In this Review, we discuss recent developments in gasdermin research with a focus on mechanisms that control gasdermin activation, pore formation and functional consequences of gasdermin-induced membrane permeabilization.
Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked ...to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin‐associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease‐causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogen‐ or host‐derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as ‘homeostasis‐altering molecular processes’ (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.
Pyrin, a pattern recognition receptor that senses inactivating modifications of RhoA GTPase that are induced by pathogens. Inactivation of RhoA leads to pyrin activation, inflammasome assembly and pyroptotic cell death. This review discusses the recently discovered activation mechanism of pyrin in the context of previous findings.
Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to ...generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1β release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis.
Recognition of microbe‐associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so‐called ...inflammasomes. Canonical inflammasomes are assembled by NOD‐like receptor (NLR) or PYHIN family members and activate caspase‐1, which promotes the induction of pyroptosis and the release of mature interleukin‐1β/‐18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase‐11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase‐11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase‐1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase‐11 controls IL‐1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase‐11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase‐11 during LPS transfection is a cell‐intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase‐11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling.
The recognition of cellular damage caused by either pathogens or abiotic stress is essential for host defense in all forms of life in the plant and animal kingdoms. The NOD-like receptors (NLRs) ...represent a large family of multidomain proteins that were initially discovered for their role in host defense in plants and vertebrates. Over recent years the wide distribution of NLRs among metazoans has become apparent and their origins have begun to emerge. Moreover, intense study of NLR function has shown that they play essential roles beyond pathogen recognition – in the regulation of antigen presentation, cell death, inflammation, and even in embryonic development. We summarize here the latest insights into NLR biology and discuss examples of converging and diverging evolution of NLR function and structure.
The non-canonical inflammasome triggers host cell death and inflammation upon recognition of cytosolic LPS. A recent report in Cell now shows that Outer Membrane Vesicles （OMVs） of extracellnlar ...Gram-negative bacteria can deliver LPS into the host cell cytosol.
Recognizing the presence of invading pathogens is key to mounting an effective innate immune response. Mammalian cells express different classes of germline-encoded pattern recognition receptors that ...monitor the extracellular and intracellular compartments of host cells for signs of infection and that activate several conserved signalling pathways. An efficient immune response often requires the sequential detection of a pathogen by different receptors in different subcellular compartments, which results in a complex interplay of downstream signalling pathways. In this Review, we discuss the recent identification of previously unknown pattern recognition receptors and how they complement the repertoire of established receptors.
Summary
Detection and clearance of invading pathogens requires a coordinated response of the adaptive and innate immune system. Host cell, however, also features different mechanisms that restrict ...pathogen replication in a cell‐intrinsic manner, collectively referred to as cell‐autonomous immunity. In immune cells, the ability to unleash those mechanisms strongly depends on the activation state of the cell, which is controlled by cytokines or the detection of pathogen‐associated molecular patterns by pattern‐recognition receptors. The interferon (IFN) class of cytokines is one of the strongest inducers of antimicrobial effector mechanisms and acts against viral, bacterial and parasitic intracellular pathogens. This has been linked to the upregulation of several hundreds of IFN‐stimulated genes, among them the so‐called IFN‐inducible GTPases. Two subfamilies of IFN‐inducible GTPases, the immunity‐related GTPases (IRGs) and the guanylate‐binding proteins (GBPs), have gained attention due to their exceptional ability to specifically target intracellular vacuolar pathogens and restrict their replication by destroying their vacuolar compartment. Their repertoire has recently been expanded to the regulation of inflammasome complexes, which are cytosolic multi‐protein complexes that control an inflammatory cell death called pyroptosis and the release of cytokines like interleukin‐1β and interleukin‐18. Here we discuss recent advances in understanding the function, the targeting and regulation of IRG and GBP proteins during microbial infections.
Abstract
The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and ...oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic
Salmonella
or upon cytosolic delivery of LPS. GBP1 associates with the surface of cytosolic
Salmonella
seconds after bacterial escape from their vacuole, initiating the recruitment of GBP2-4 to assemble a GBP coat. The GBP coat then promotes the recruitment of caspase-4 to the bacterial surface and caspase activation, in absence of bacteriolysis. Mechanistically, GBP1 binds LPS with high affinity through electrostatic interactions. Our findings indicate that in human epithelial cells GBP1 acts as a cytosolic LPS sensor and assembles a platform for caspase-4 recruitment and activation at LPS-containing membranes as the first step of non-canonical inflammasome signaling.
Inflammasomes control host cell death and inflammation in response to sterile or infectious stimuli. Two recent reports published in Science reveal the structural basis for the assembly of NAIP-NLRC4 ...inflammasomes.
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