Cell-autonomous and non-cell-autonomous functions of caspase-8

Moshe, Tehila Ben; Kang, Tae-Bong; Kovalenko, Andrew; Barash, Hila; Abramovitch, Rinat; Galun, Eithan; Wallach, David

doi:10.1016/j.cytogfr.2008.04.012

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…However, caspase-8 also serves various nonapoptotic functions (Ben Moshe et al, 2008). Our finding here points to a possible general mode of action by which this protease serves nonapoptotic functions.…”

Section: Introductionmentioning

confidence: 83%

RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

et al. 2011

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Excessive responses to pattern-recognition receptors are prevented by regulatory mechanisms that affect the amounts and activities of the downstream signaling proteins. We report that activation of the transcription factor IRF3 by the ribonucleic acid sensor RIG-I was restricted by caspase-8-mediated cleavage of the RIP1 protein, which resulted in conversion of RIP1 from a signaling enhancer to a signaling inhibitor. The proteins RIP1 and caspase-8 were recruited to the RIG-I complex after viral infection and served antagonistic regulatory roles. Conjugation of ubiquitin chains to RIP1 facilitated assembly of the RIG-I complex, resulting in enhanced phosphorylation of IRF3. However, the ubiquitination of RIP1 also rendered it susceptible to caspase-8-mediated cleavage that yielded an inhibitory RIP1 fragment. The dependence of RIP1 cleavage on the same molecular change as that facilitating RIG-I signaling allows for RIG-I signaling to be restricted in its duration without compromising its initial activation.

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Section: Introductionmentioning

confidence: 83%

RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

et al. 2011

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“…It should be noted however that humans contain an additional caspase not produced in mice, namely caspase 10, that may be functionally redundant with caspase 8. Therefore, therapeutic strategies should also consider caspase 10, which is structurally and functionally highly similar to caspase 8 (reviewed in [89]), and thus likely to be sensitive to the same interventions that neutralize caspase 8.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

et al. 2011

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BackgroundAcute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8 −/−), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system.Methodology/Principal FindingsCaspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8 −/− mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.ConclusionsNeuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma.

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“…Since no ligand of the TNF family serves any vital role, this finding was unexpected, and it raised the possibility that caspase‐8 also serves functions that are unrelated to the activity of these ligands and perhaps distinct from its role in death induction. Subsequent studies in mice with conditional knockout of caspase‐8 confirmed that this enzyme indeed serves various nonapoptotic functions 18 …”

Section: Direct Regulation Of Inflammation By Caspase‐8mentioning

confidence: 97%

“…Subsequent studies in mice with conditional knockout of caspase-8 confirmed that this enzyme indeed serves various nonapoptotic functions. 18 On examining the functional consequences of caspase-8 deletion in hepatocytes, we noticed that partial hepatectomy in these mice prompted hypertrophy of the liver. This response could be ascribed to the development of a chronic inflammatory state.…”

Section: Direct Regulation Of Inflammation By Caspase-8mentioning

confidence: 99%

Anti‐inflammatory functions of the “apoptotic” caspases

Wallach

Kang

Rajput

et al. 2010

Annals of the New York Academy of Sciences

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The two main known functions of the caspases act antagonistically in regulating inflammation. "Inflammatory" caspases trigger inflammation by catalyzing the processing of IL-1β precursors and other proinflammatory cytokines. In contrast, "apoptotic" caspases safeguard against the triggering of inflammation by imposing a cell-death form that withholds release of alarmins by dying cells and dictates generation of anti-inflammatory mediators. These antagonizing functions are exerted by evolution-related mechanisms. Studies of the function of caspase-8, an enzyme-mediating apoptotic cell-death induction in response to TNF-family ligands, reveal that it blocks inflammation in additional ways. One way is by restricting activation of the RIG-I complex by foreign ribonucleic acid. Chronic skin inflammation in mice with caspase-8-deficient epidermis is associated with constitutive activation of the RIG-I complex in keratinocytes. This activation is apparently prompted by nucleic acids released from epidermal cells that disintegrate during cornification, and becomes chronic because it is not restricted by caspase-8.

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Cell-autonomous and non-cell-autonomous functions of caspase-8

Cited by 10 publications

References 33 publications

RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

Anti‐inflammatory functions of the “apoptotic” caspases

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