Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice

Saleh, Maya; Mathison, John C.; Wolinski, Melissa K.; Bensinger, Steve J.; Fitzgerald, Patrick; Droin, Nathalie; Ulevitch, Richard J.; Green, Douglas R.; Nicholson, Donald W.

doi:10.1038/nature04656

Cited by 289 publications

(306 citation statements)

References 18 publications

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“…39,40 Whereas degradation or proteolysis of caspase-12 is a well-established hallmark of ER stress, its central role in ER-stress-induced apoptosis was challenged by various studies. [41][42][43] The precise function of caspase-12 in this particular pathway is yet unclear and controversial.…”

Section: Caspase-1 and It Substrate Il-1bmentioning

confidence: 99%

“…9,10 In line with this hypothesis, caspase-12-deficient mice were shown to clear bacterial infection more efficiently than wild-type littermates and have an enhanced production of the pro-inflammatory cytokines IL-1b and IL-18 but not TNF and IL-6. 43 Mechanistically, caspase-12 was proposed to be a decoy caspase that blocks caspase-1 activation resulting in enhanced vulnerability to bacterial infection and septic mortality, plausibly in the same way as cFLIP (a decoy caspase-8-like protein) regulates caspase-8-mediated apoptosis 43 (see the accompanying review by Maya Saleh).…”

Section: Caspase-1 and It Substrate Il-1bmentioning

confidence: 99%

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Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-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. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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Section: Caspase-1 and It Substrate Il-1bmentioning

confidence: 99%

Section: Caspase-1 and It Substrate Il-1bmentioning

confidence: 99%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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“…There is evidence that caspase-12 deficiency in mice renders them resistant to peritonitis and septic shock, though the mechanisms appear more to be anti-inflammatory in nature [15]. The relevance of this pathway as a disease mechanism during sepsis still needs to be elucidated.…”

Section: Mechanisms Of Apoptosis -Many Ways To Diementioning

confidence: 99%

Role of programmed cell death in the immunopathogenesis of sepsis

Perl

Chung

Swan

et al. 2007

Drug Discovery Today: Disease Mechanisms

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Apoptosis is an important mechanism during the immunopathogenesis of sepsis. Early programmed cell death of lymphocytes substantially impairs innate and adaptive immunity reducing the capacity to ward off the invading pathogen. Apoptosis of parenchymal cells (e.g. in the lung, liver and gut) may also promote organ failure and death. Several experimental therapeutic strategies have now been developed to beneficially influence these mechanisms; however, their potential clinical benefit is yet to be evaluated.

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“…9 Additionally, human caspase 12 lacks protease activity, bringing into question the relative importance of the caspase 12 pathway in ER stressinduced apoptosis. 12,13 Recent studies suggest that the mitochondrial pathway may be significant in either inducing or amplifying ER stress-induced apoptosis. First, in contrast to the data in C2C12 cells, cytochrome c is released in response to ER stress in a variety of other cell types.…”

mentioning

confidence: 99%

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

Smith

Deshmukh

2007

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stressinducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3-only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c-jun N-terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf-1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress-induced apoptosis and clarify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.

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Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice

Cited by 289 publications

References 18 publications

Inflammatory caspases and inflammasomes: master switches of inflammation

Inflammatory caspases and inflammasomes: master switches of inflammation

Role of programmed cell death in the immunopathogenesis of sepsis

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

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