scholarly journals Caspase-1 interdomain linker cleavage is required for pyroptosis

2020 ◽  
Vol 3 (3) ◽  
pp. e202000664 ◽  
Author(s):  
Daniel P Ball ◽  
Cornelius Y Taabazuing ◽  
Andrew R Griswold ◽  
Elizabeth L Orth ◽  
Sahana D Rao ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Pattern Recognition Receptors ◽  
Adapter Protein ◽  
Large Structure ◽  
Catalytic Subunits ◽  
Caspase 1 ◽  
Interdomain Linker

Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller “ASC-independent” inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes.

scholarly journals Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation

2019 ◽  
Author(s):  
Daniel P. Ball ◽  
Cornelius Y. Taabazuing ◽  
Andrew R. Griswold ◽  
Elizabeth L. Orth ◽  
Sahana D. Rao ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Pattern Recognition Receptors ◽  
Inflammasome Activation ◽  
Adapter Protein ◽  
Large Structure ◽  
Catalytic Subunits ◽  
Caspase 1 ◽  
Human Caspase

AbstractPathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied PRRs oligomerize with the pro-caspase-1-adapter protein ASC to generate a single large structure in the cytosol, which induces the autoproteolysis and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming much smaller “ASC-independent” inflammasomes. It is currently thought that pro-caspase-1 autoproteolysis does not occur during, and is not required for, ASC-independent inflammasome activation. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first PRR that cannot form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is an obligate regulatory step in the activation of human canonical inflammasomes.

scholarly journals Pattern Recognition Receptors and the Host Cell Death Molecular Machinery

2018 ◽  
Vol 9 ◽  
Author(s):  
Gustavo P. Amarante-Mendes ◽  
Sandy Adjemian ◽  
Laura Migliari Branco ◽  
Larissa C. Zanetti ◽  
Ricardo Weinlich ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Host Cell ◽  
Pattern Recognition Receptors ◽  
Host Cell Death ◽  
Molecular Machinery

Inhibitory pattern recognition receptors

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Matevž Rumpret ◽  
Helen J. von Richthofen ◽  
Victor Peperzak ◽  
Linde Meyaard
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Immune System ◽  
Immune Responses ◽  
Pattern Recognition Receptors ◽  
Inhibitory Receptors ◽  
Danger Signals ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathogen- and damage-associated molecular patterns are sensed by the immune system’s pattern recognition receptors (PRRs) upon contact with a microbe or damaged tissue. In situations such as contact with commensals or during physiological cell death, the immune system should not respond to these patterns. Hence, immune responses need to be context dependent, but it is not clear how context for molecular pattern recognition is provided. We discuss inhibitory receptors as potential counterparts to activating pattern recognition receptors. We propose a group of inhibitory pattern recognition receptors (iPRRs) that recognize endogenous and microbial patterns associated with danger, homeostasis, or both. We propose that recognition of molecular patterns by iPRRs provides context, helps mediate tolerance to microbes, and helps balance responses to danger signals.

scholarly journals Platelet activation by charged ligands and nanoparticles: platelet glycoprotein receptors as pattern recognition receptors

Platelets ◽  
2021 ◽  
pp. 1-13
Author(s):  
Samantha J. Montague ◽  
Pushpa Patel ◽  
Eleyna M. Martin ◽  
Alexandre Slater ◽  
Lourdes Garcia Quintanilla ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Platelet Activation ◽  
Pattern Recognition Receptors ◽  
Platelet Glycoprotein ◽  
Charged Ligands

scholarly journals VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Zhezhe Sun ◽  
Mark Nyanzu ◽  
Su Yang ◽  
Xiaohong Zhu ◽  
Kankai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Blood Brain Barrier ◽  
High Mobility ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Nf Kappa B ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Area Of Interest ◽  
Blood Brain

Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

scholarly journals Pattern recognition receptors: A contemporary view on liver diseases

Hepatology ◽  
2006 ◽  
Vol 44 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Gyongyi Szabo ◽  
Angela Dolganiuc ◽  
Pranoti Mandrekar
Keyword(s):  
Pattern Recognition ◽  
Liver Diseases ◽  
Pattern Recognition Receptors ◽  
Contemporary View
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