Abstract:Highlights d Development of two microscopy assays for microbe/ microbe-containing vacuole lysis d Human GBP1 is essential for the lysis of Toxoplasma gondii vacuoles and parasites d Caspase-4 recruitment, but not cytosolic escape of Salmonella, is GBP1 dependent d Caspase-1 cleaves and inactivates GBP1 and suppresses caspase-4-driven pyroptosis
“…For example, GBP1 was recently proposed to act as a microbe-specific switch enabling recognition of either Toxoplasma gondii DNA, inducing apoptosis through AIM2, or Salmonella LPS, instead promoting pyroptosis via caspase-4. 301 , 302 Fig. 4 Crossing lines of programmed cell death.…”
Section: Crossing Lines Of Regulated Cell Deathmentioning
Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.
“…For example, GBP1 was recently proposed to act as a microbe-specific switch enabling recognition of either Toxoplasma gondii DNA, inducing apoptosis through AIM2, or Salmonella LPS, instead promoting pyroptosis via caspase-4. 301 , 302 Fig. 4 Crossing lines of programmed cell death.…”
Section: Crossing Lines Of Regulated Cell Deathmentioning
Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.
“…This group discovered that hGBP1 recruitment to C. trachomatis inclusions activates GTP hydrolysis to GMP and the subsequent generation of uric acid activates the NLRP3 inflammasome [125]. This novel pathway suggests that, in contrast with previous findings [69,[94][95][96][97], inflammasome activation can be independent of PAMP release in human cells, relying only on the hydrolytic activity of hGBP1 [125]. Whether this activation is unique to the Chlamydia inclusion or represents a more general response towards other pathogens, remains to be investigated.…”
“…GBPs and IRGs are typically found in the cytosol, in vesicle-like structures and on endomembranes, but translocate to pathogen compartments and cytosolic bacteria which have escaped from the phagosome (Figure 1) [70,75,82,83]. Bacteria shown to interact with GBPs and IRGs include Listeria monocytogenes, Legionella pneumophila, Shigella flexneri, Mycobacterium bovis BCG, Chlamydia trachomatis, Francisella novicida, Salmonella typhimurium, Brucella abortus, Yersinia pseudotuberculosis and Burkholderia thailandensis [2,[38][39][40][42][43][44]47,56,65,69,[84][85][86][87][88][89][90][91][92][93][94][95][96].…”
Section: Targeting Of Specific Pathogens By Gbps and Irgsmentioning
confidence: 99%
“…Besides the co-localisation of GBPs and IRGs with particular pathogens, differences in GBP targeting of the same pathogens have also been observed in distinct cell types of the same host species. For example, hGBP1 co-localises with T. gondii in mesenchymal stromal cells and THP1 but not A549 cells [ 69 , 96 , 110 , 111 ]. This remarkable diversity of targeting strategies for specific pathogens might be due to the diverse genetic backgrounds and proteomes of different host species and cell types as well as pathogen-specific virulence factors and intracellular life cycles.…”
Section: Mechanisms Of Host Defence By Ifn-induced Gtpasesmentioning
Interferon (IFN)-induced guanosine triphosphate hydrolysing enzymes (GTPases) have been identified as cornerstones of IFN-mediated cell-autonomous defence. Upon IFN stimulation, these GTPases are highly expressed in various host cells, where they orchestrate anti-microbial activities against a diverse range of pathogens such as bacteria, protozoan and viruses. IFN-induced GTPases have been shown to interact with various host pathways and proteins mediating pathogen control via inflammasome activation, destabilising pathogen compartments and membranes, orchestrating destruction via autophagy and the production of reactive oxygen species as well as inhibiting pathogen mobility. In this mini-review, we provide an update on how the IFN-induced GTPases target pathogens and mediate host defence, emphasising findings on protection against bacterial pathogens.
“…Interferon-inducible guanylate binding proteins (GBPs) [58] recognise the outer section of LPS on cytosolic bacteria and allow for the assembly of an inflammasome directly on the bacteria. In human epithelial cells, this assembly platform is composed of GBP1, 2, 3 and 4 [54][55][56]59]. Outer membrane vesicles [60] can also activate the non-canonical inflammasome in a GBP-dependant manner [61].…”
Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.
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