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Junying Yuan - One of the best experts on this subject based on the ideXlab platform.

  • Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1.
    Cell Reports, 2014
    Co-Authors: Mingzhi Jin, Bimal N Desai, Anirudh Penumaka, Hong Zhu, Maike Kober, Alexander Dietrich, Marta M Lipinski, Thomas Henry, David E Clapham, Junying Yuan
    Abstract:

    Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of Caspase-11 in regulating inflammation because the known substrates of Caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of Caspase-11. TRPC1 deficiency increases the secretion of IL-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1β secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that Caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.

  • caspase 11 regulates cell migration by promoting aip1 cofilin mediated actin depolymerization
    Nature Cell Biology, 2007
    Co-Authors: Juying Li, William M Brieher, Lucila M Scimone, Shin Jung Kang, Ulrich H Von Andrian, Timothy J. Mitchison, Junying Yuan
    Abstract:

    Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that Caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo. We demonstrate that Caspase-11 interacts physically and functionally with actin interacting protein 1 (Aip1), an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain (CARD) of Caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or Caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that Caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho–Rac–Cdc42 pathway.

  • Caspase-11 regulates cell migration by promoting Aip1–Cofilin-mediated actin depolymerization
    Nature Cell Biology, 2007
    Co-Authors: William M Brieher, Shin Jung Kang, Hong Zhu, M. Lucila Scimone, Helen Yin, Ulrich H. Von Andrian, Timothy Mitchison, Junying Yuan
    Abstract:

    Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that Caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo . We demonstrate that Caspase-11 interacts physically and functionally with actin interacting protein 1 (Aip1), an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain (CARD) of Caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or Caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that Caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho–Rac–Cdc42 pathway.

  • Dissociation between Neurodegeneration and Caspase-11-Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
    Co-Authors: Shin Jung Kang, Ivelisse Sánchez, Naisen Jing, Junying Yuan
    Abstract:

    Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of Caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1β, were significantly reduced in the spinal cord of symptomatic Caspase-11 –/–;SOD1 G93A mice compared with that of Caspase-11 +/–; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of Caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.

  • Distinct downstream pathways of Caspase-11 in regulating apoptosis and cytokine maturation during septic shock response
    Cell death and differentiation, 2002
    Co-Authors: S J Kang, Keisuke Kuida, S Wang, Junying Yuan
    Abstract:

    Caspase-11 is an essential mediator of septic shock response and Caspase-11-deficient mice are resistant to LPS-induced shock. Here we report that LPS-induced Caspase-11 regulates lymphocyte apoptosis by activating both caspase-3 and caspase-7. The activation of Caspase-11 preceded that of caspase-1 and caspases-3/-7, and in the absence of Caspase-11, the activation of caspases-3/-7 was significantly reduced. The early activation of caspases-3/-7 by Caspase-11 was not affected by blocking of caspase-1 activity and IL-1β release, implying that Caspase-11 activates caspases-3/-7 independently of caspase-1 activation. Furthermore, we show that Caspase-11-mediated apoptosis under septic condition is Bid-independent. Our work suggests that the human homologue of Caspase-11 may be an effective therapeutic target for treatment of septic shock.

Shin Jung Kang - One of the best experts on this subject based on the ideXlab platform.

  • The involvement of Caspase-11 in TPEN-induced apoptosis.
    FEBS letters, 2008
    Co-Authors: Jong Min Lee, Shin Jung Kang, Yu-jin Kim, Seung Jin Han, Jae-young Koh, Yang-hee Kim
    Abstract:

    The depletion of intracellular zinc with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induces protein synthesis-dependent apoptosis. Here we examined the involvement of caspase induction in apoptosis. Among the examined caspases, only Caspase-11 was increased by TPEN. Caspase-11 activity also increased, which resulted in caspase-3 activation. Cycloheximide or actinomycin D blocked Caspase-11 induction, reduced Caspase-11 and -3 activation, and attenuated TPEN-induced neuronal apoptosis. Blockade of Caspase-11 by a chemical inhibitor or genetic deletion attenuated TPEN-induced apoptosis, indicating a critical role of Caspase-11 in TPEN-induced apoptosis. Although mitochondria-mediated caspase-9/-3 activation also contributed to TPEN-induced apoptosis, Caspase-11 is likely a key inducible apoptosis-inducing protein.

  • caspase 11 regulates cell migration by promoting aip1 cofilin mediated actin depolymerization
    Nature Cell Biology, 2007
    Co-Authors: Juying Li, William M Brieher, Lucila M Scimone, Shin Jung Kang, Ulrich H Von Andrian, Timothy J. Mitchison, Junying Yuan
    Abstract:

    Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that Caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo. We demonstrate that Caspase-11 interacts physically and functionally with actin interacting protein 1 (Aip1), an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain (CARD) of Caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or Caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that Caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho–Rac–Cdc42 pathway.

  • Caspase-11 regulates cell migration by promoting Aip1–Cofilin-mediated actin depolymerization
    Nature Cell Biology, 2007
    Co-Authors: William M Brieher, Shin Jung Kang, Hong Zhu, M. Lucila Scimone, Helen Yin, Ulrich H. Von Andrian, Timothy Mitchison, Junying Yuan
    Abstract:

    Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that Caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo . We demonstrate that Caspase-11 interacts physically and functionally with actin interacting protein 1 (Aip1), an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain (CARD) of Caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or Caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that Caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho–Rac–Cdc42 pathway.

  • Dissociation between Neurodegeneration and Caspase-11-Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
    Co-Authors: Shin Jung Kang, Ivelisse Sánchez, Naisen Jing, Junying Yuan
    Abstract:

    Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of Caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1β, were significantly reduced in the spinal cord of symptomatic Caspase-11 –/–;SOD1 G93A mice compared with that of Caspase-11 +/–; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of Caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.

  • Dual role of Caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions.
    The Journal of cell biology, 2000
    Co-Authors: Shin Jung Kang, Suyue Wang, Hideaki Hara, Erin P. Peterson, Shobu Namura, Sepideh Amin-hanjani, Zhihong Huang, Anu Srinivasan, Kevin J. Tomaselli, Nancy A. Thornberry
    Abstract:

    Caspase-11, a member of the murine caspase family, has been shown to be an upstream activator of caspase-1 in regulating cytokine maturation. We demonstrate here that in addition to its defect in cytokine maturation, Caspase-11–deficient mice have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion (MCAO), a mouse model of stroke. Recombinant proCaspase-11 can autoprocess itself in vitro. Purified active recombinant Caspase-11 cleaves and activates procaspase-3 very efficiently. Using a positional scanning combinatorial library method, we found that the optimal cleavage site of Caspase-11 was (I/L/V/P)EHD, similar to that of upstream caspases such as caspase-8 and -9. Our results suggest that Caspase-11 is a critical initiator caspase responsible for the activation of caspase-3, as well as caspase-1 under certain pathological conditions.

Feng Shao - One of the best experts on this subject based on the ideXlab platform.

  • Innate immunity to intracellular LPS
    Nature Immunology, 2019
    Co-Authors: Vijay A K Rathinam, Yue Zhao, Feng Shao
    Abstract:

    Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, Caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of Caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called ‘pyroptosis’, which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by Caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions. Comprehensive immunity requires that cells sense intracellular pathogens. In their Review, Shao and colleagues describe mechanisms for the recognition of intracellular lipopolysaccharide and its essential role in responses to Gram-negative bacteria.

  • Inflammatory Caspases: Activation and Cleavage of Gasdermin-D In Vitro and During Pyroptosis
    Innate Immune Activation, 2018
    Co-Authors: Yue Zhao, Jianjin Shi, Feng Shao
    Abstract:

    Gasdermin-D (also known as GSDMD), the newly identified executioner of pyroptotic cell death, is cleaved by activated caspase-1 downstream of canonical inflammasome activation or caspase-4, 5, and 11 upon their ligation and activation by cytosolic LPS. Upon a single cleavage between the two domains in Gasdermin-D, the N-terminal domain binds to membrane lipids and lyses cells by forming pores of an inner diameter of 10–14 nm within the membrane. The inter-domain cleavage of Gasdermin-D is a reliable marker for the activation of inflammatory caspases and cell pyroptosis. Here, we describe the methods for examining Gasdermin-D cleavage by activated inflammatory caspases in vitro and upon inflammasome activation in vivo.

  • cleavage of gsdmd by inflammatory caspases determines pyroptotic cell death
    Nature, 2015
    Co-Authors: Jianjin Shi, Yue Zhao, Kun Wang, Xuyan Shi, Yue Wang, Huanwei Huang, Yinghua Zhuang, Tao Cai, Fengchao Wang, Feng Shao
    Abstract:

    Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of Caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

  • non canonical activation of inflammatory caspases by cytosolic lps in innate immunity
    Current Opinion in Immunology, 2015
    Co-Authors: Jieling Yang, Yue Zhao, Feng Shao
    Abstract:

    Lipopolysaccharide (LPS) is the major component of Gram-negative bacteria cell wall. In innate immunity, extracellular LPS is recognized by Toll-like receptor 4 to stimulate cytokine transcription. Recent studies suggest a ‘non-canonical inflammasome’ that senses cytoplasmic LPS and activates Caspase-11 in mouse macrophages. Unexpectedly, biochemical studies reveal that Caspase-11 and its human orthologs caspase-4/caspase-5 are LPS receptors themselves. Direct LPS binding induces caspase-4/caspase-5/Caspase-11 oligomerization and activation, triggering cell pyroptosis and anti-bacterial defenses. Caspase-4/caspase-5/Caspase-11 recognition of intracellular LPS requires bacterial escape from the vacuole; this process is promoted by interferon-inducible GTPases-mediated lysis of the bacteria-containing vacuole. Non-canonical activation of these inflammatory caspases by LPS not only represents a new paradigm in innate immunity but also critically determines LPS-induced septic shock in mice.

  • inflammatory caspases are innate immune receptors for intracellular lps
    Nature, 2014
    Co-Authors: Yue Zhao, Liyan Hu, Jingjin Ding, Yupeng Wang, Peng Li, Feng Shao
    Abstract:

    The murine Caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine Caspase-11. Human caspase-4 and the mouse homologue Caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous Caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation. Caspase-4 and Caspase-11 are shown to be the direct sensors for cytoplasmic lipopolysaccharide in humans and mice, respectively, mediating inflammatory cell death in intracellular bacterial infection. A 'non-canonical' innate immune pathway, independent of Toll-like receptor 4 but involving Caspase-11, was recently discovered in mice, where it acts to recognize lipopolysaccharide (LPS) from pathogenic bacteria. Here Feng Shao and colleagues investigate this pathway and a similar one in humans. They find that Caspase-11 and caspase-4 are the direct sensors for cytoplasmic LPS in mice and humans, respectively, mediating inflammatory cell death in intracellular bacterial infection.

Edward A Miao - One of the best experts on this subject based on the ideXlab platform.

  • caspase 11 mediated endothelial pyroptosis underlies endotoxemia induced lung injury
    Journal of Clinical Investigation, 2017
    Co-Authors: Kwong Tai Cheng, Edward A Miao, Shiqin Xiong, Zhigang Hong, Kit Man Tsang, Xiaopei Gao, Manish Mittal, Stephen M Vogel, Jalees Rehman, Asrar B Malik
    Abstract:

    Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog Caspase-11 in mice in vivo. In Caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic Caspase-11 in endotoxemia. Additionally, conditional deletion of Caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.

  • canonical inflammasomes drive ifn γ to prime caspase 11 in defense against a cytosol invasive bacterium
    Cell Host & Microbe, 2015
    Co-Authors: Youssef Aachoui, Irina A Leaf, Alan Aderem, Yuji Kajiwara, Jenny P Y Ting, Jorn Coers, Joseph D Buxbaum, Edward A Miao
    Abstract:

    Summary The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that Caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis , we find that caspase-1 activity is required upstream of Caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime Caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime Caspase-11. Although mice transgenic for caspase-4, the human ortholog of Caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of Caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium.

  • Cytoplasmic LPS activates Caspase-11: implications in TLR4-independent endotoxic shock (INM6P.406)
    Journal of Immunology, 2014
    Co-Authors: Edward A Miao, Jon A Hagar, Daniel A Powell, Youssef Aachoui, Robert K Ernst
    Abstract:

    Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive Caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers Caspase-11 activation in mice. Specifically, Caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the Caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild type and Tlr4-deficient mice, whereas caspase 11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS.

  • cytoplasmic lps activates caspase 11 implications in tlr4 independent endotoxic shock
    Science, 2013
    Co-Authors: Jon A Hagar, Daniel A Powell, Youssef Aachoui, Robert K Ernst, Edward A Miao
    Abstract:

    Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive Caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers Caspase-11 activation in mice. Specifically, Caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the Caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild-type and Tlr4-deficient mice, whereas Casp11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS.

Fabio Martinon - One of the best experts on this subject based on the ideXlab platform.

  • Pyroptosis: Caspase-11 Unlocks the Gates of Death
    Immunity, 2015
    Co-Authors: Aude De Gassart, Fabio Martinon
    Abstract:

    How inflammatory caspases trigger pyroptotic cell death is mostly unexplained. In this issue of Immunity, Nunez and colleagues report that Caspase-11 cleaves the transmembrane channel pannexin-1, causing an efflux of cellular ATP that promotes a P2X7 receptor-dependent pyroptosis.

  • Inflammatory caspases and inflammasomes: master switches of inflammation
    Cell Death & Differentiation, 2007
    Co-Authors: Fabio Martinon, Jurg Tschopp
    Abstract:

    Fifteen years have passed since the cloning and characterization of the interleukin-1 β -converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction.

  • The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
    Molecular Cell, 2002
    Co-Authors: Fabio Martinon, Kimberly Burns, Jurg Tschopp
    Abstract:

    Generation of Interleukin (IL)-1beta via cleavage of its proform requires the activity of caspase-1 (and Caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive. Here we report the identification of a caspase-activating complex that we call the inflammasome. The inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs. Using a cell-free system, we show that proinflammatory caspase activation and proIL-1beta processing is lost upon prior immunodepletion of Pycard. Moreover, expression of a dominant-negative form of Pycard in differentiated THP-1 cells blocks proIL-1beta maturation and activation of inflammatory caspases induced by LPS in vivo. Thus, the inflammasome constitutes an important arm of the innate immunity.

  • the inflammasome a molecular platform triggering activation of inflammatory caspases and processing of proil beta
    Molecular Cell, 2002
    Co-Authors: Fabio Martinon, Kimberly Burns, Jurg Tschopp
    Abstract:

    Abstract Generation of Interleukin (IL)-1β via cleavage of its proform requires the activity of caspase-1 (and Caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive. Here we report the identification of a caspase-activating complex that we call the inflammasome. The inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs. Using a cell-free system, we show that proinflammatory caspase activation and proIL-1β processing is lost upon prior immunodepletion of Pycard. Moreover, expression of a dominant-negative form of Pycard in differentiated THP-1 cells blocks proIL-1β maturation and activation of inflammatory caspases induced by LPS in vivo. Thus, the inflammasome constitutes an important arm of the innate immunity.