Bcl-2 and Bcl-XL Regulate Proinflammatory Caspase-1 Activation by Interaction with NALP1

Bruey, Jean‐Marie; Bruey-Sédano, Nathalie; Luciano, Fréderic; Zhai, Dayong; Balpai, Ruchi; Xu, Chunyan; Kress, Christina L.; Bailly-Maître, Béatrice; Li, Xiaoqing; Osterman, Andrei L.; Matsuzawa, Shu‐ichi; Terskikh, Alexey V.; Faustin, Benjamin; Reed, John C.

doi:10.1016/j.cell.2007.01.045

Cited by 295 publications

(240 citation statements)

References 32 publications

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“…For example, although cellular Bcl-2 has a central function related to its binding to the BH3 domains of proapoptotic Bcl-2 family proteins, it also interacts with a variety of cellular proteins, including inositol triphosphate receptors, Bax inhibitor-1, bifunctional apoptosis regulator, and Bap31 in membranes of the endoplasmic reticulum (reviewed in Refs. 20 and 51), and with the autophagy protein Beclin (52) as well as also directly binding and suppressing cytosolic NLR family proteins such as NALP1 (NLRP1) (53). It will be interesting therefore to explore whether F1L has additional unrecognized cellular targets analogous to cellular Bcl-2.…”

Section: Discussionmentioning

confidence: 99%

Vaccinia Virus Protein F1L Is a Caspase-9 Inhibitor

Zhai¹,

Yu²,

Jin

et al. 2010

Journal of Biological Chemistry

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Apoptosis plays important roles in host defense, including the elimination of virus-infected cells. The executioners of apoptosis are caspase family proteases. We report that vaccinia virusencoded F1L protein, previously recognized as anti-apoptotic viral Bcl-2 family protein, is a caspase-9 inhibitor. F1L binds to and specifically inhibits caspase-9, the apical protease in the mitochondrial cell death pathway while failing to inhibit other caspases. In cells, F1L inhibits apoptosis and proteolytic processing of caspases induced by overexpression of caspase-9 but not caspase-8. An N-terminal region of F1L preceding the Bcl-2-like fold accounts for caspase-9 inhibition and significantly contributes to the anti-apoptotic activity of F1L. Viral F1L thus provides the first example of caspase inhibition by a Bcl-2 family member; it functions both as a suppressor of proapoptotic Bcl-2 family proteins and as an inhibitor of caspase-9, thereby neutralizing two sequential steps in the mitochondrial cell death pathway.Viruses have evolved multiple strategies to prevent or delay host anti-viral responses. Apoptosis is a host mechanism used to combat viral infections by eliminating virus-producing cells. By inhibiting apoptosis, viruses can ensure adequate time to replicate their genomes, as well as providing a possible mechanism for achieving chronic latent infections. Suppression of apoptosis can also contribute to escape from host immune surveillance, allowing virus-infected cells to withstand attack by cytolytic T-cells and thus continue viral production (1, 2).Viruses have either evolved independently or usurped from host cells a diversity of anti-apoptotic strategies. Apoptosis is mediated by caspases, a family of intracellular cysteine proteases. Consequently, viruses often target either the caspases or their upstream cellular activators. For example, viral homologs of anti-apoptotic Bcl-2 family proteins have been identified in poxviruses, herpesviruses, adenoviruses, and other viruses. These proteins suppress a major pathway for caspase activation and cell death that involves mitochondria, which is often referred to as the "intrinsic" pathway (reviewed in Ref.3). Multiple signals converge on mitochondria, including DNA damage, hypoxia, and oxidative stress, which modulate the expression or activity of various cellular Bcl-2 family proteins that associate with these organelles. Bcl-2 family proteins either block or cause the release of cytotoxic mitochondrial proteins including cytochrome c, which binds to and induces oligomerization of Apaf1, a central component of a caspase-9-activating complex known as the "apoptosome" (1, 2, 4). Activation of apoptosome-associated caspase-9 initiates a proteolytic cascade whereby activated caspase-9 cleaves and activates downstream executioner proteases such as procaspase-3 and -7, resulting in apoptotic cell demise. Viruses encode homologs of cellular anti-apoptotic Bcl-2 proteins to protect infected host cells by keeping the mitochondria intact, and several viral Bcl-2 protein...

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Section: Discussionmentioning

confidence: 99%

Vaccinia Virus Protein F1L Is a Caspase-9 Inhibitor

Zhai¹,

Yu²,

Jin

et al. 2010

Journal of Biological Chemistry

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“…40 Here, we demonstrate that the AIM2/ASC complex can activate caspase-8. Taken together, these results highlight the interplay between the inflammasome pathway and the apoptotic machinery and illustrate the possible switch between apoptotic and pyroptotic pathways upon PRR engagement.…”

Section: Aim2/asc-dependent Caspase-8-mediated Apoptosis R Pierini Ementioning

confidence: 99%

AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages

Pierini¹,

Juruj²,

Perret³

et al. 2012

Cell Death Differ

226

203

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The inflammasome is a signalling platform leading to caspase-1 activation. Caspase-1 causes pyroptosis, a necrotic-like cell death. AIM2 is an inflammasome sensor for cytosolic DNA. The adaptor molecule ASC mediates AIM2-dependent caspase-1 activation. To date, no function besides caspase-1 activation has been ascribed to the AIM2/ASC complex. Here, by comparing the effect of gene inactivation at different levels of the inflammasome pathway, we uncovered a novel cell death pathway activated in an AIM2/ASC-dependent manner. Francisella tularensis, the agent of tularaemia, triggers AIM2/ASC-dependent caspase-3-mediated apoptosis in caspase-1-deficient macrophages. We further show that AIM2 engagement leads to ASCdependent, caspase-1-independent activation of caspase-8 and caspase-9 and that caspase-1-independent death is reverted upon caspase-8 inhibition. Caspase-8 interacts with ASC and active caspase-8 specifically colocalizes with the AIM2/ASC speck thus identifying the AIM2/ASC complex as a novel caspase-8 activation platform. Furthermore, we demonstrate that caspase-1-independent apoptosis requires the activation of caspase-9 and of the intrinsic pathway in a typical type II cell manner. Finally, we identify the AIM2/ASC-dependent caspase-1-independent pathway as an innate immune mechanism able to restrict bacterial replication in vitro and control IFN-c levels in vivo in Casp1 KO mice. This work underscores the crosstalk between inflammasome components and the apoptotic machinery and highlights the versatility of the pathway, which can switch from pyroptosis to apoptosis.

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“…Moreover, Nfe2l2 Ϫ/Ϫ mice show impaired NRF-1 and PGC-1␣ gene activation and fail to increase anti-inflammatory IL-10, Socs3, or Bcl XL expression in the E. coli model. Lack of Bcl XL expression increases the risk of intrinsic apoptosis (69) but also suppresses caspase-1-dependent IL-1␤ processing by interaction with NALD1 (70). Furthermore, low dose CO, similar to other cell-protective CO therapy (71), improves survival in the sepsis model in WT, but not Nfe2l2-deficient mice.…”

Section: Was Detected (Panels A-c) Dcm/co (1-h Exposure) Caused Robumentioning

confidence: 99%

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

Piantadosi

Withers

Bartz

et al. 2011

Journal of Biological Chemistry

231

184

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The induction of heme oxygenase-1 (HO-1; Hmox1) by inflammation, for instance in sepsis, is associated both with an anti-inflammatory response and with mitochondrial biogenesis. Here, we tested the idea that HO-1, acting through the Nfe2l2 (Nrf2) transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO-1 induction after LPS stimulated anti-inflammatory IL-10 and IL-1 receptor antagonist (IL-1Ra) expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-␣ expression. This was accompanied by nuclear Nfe2l2 accumulation and led us to identify abundant Nfe2l2 and other mitochondrial biogenesis transcription factor binding sites in the promoter regions of IL10 and IL1Ra compared with pro-inflammatory genes regulated by NF-〉. Mechanistically, HO-1, through its CO product, enabled these transcription factors to bind the core IL10 and IL1Ra promoters, which for IL10 included Nfe2l2, nuclear respiratory factor (NRF)-2 (Gabpa), and MEF2, and for IL1Ra, included NRF-1 and MEF2. In cells, Hmox1 or Nfe2l2 RNA silencing prevented IL-10 and IL-1Ra up-regulation, and HO-1 induction failed post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2 ؊/؊ mice. Nfe2l2 ؊/؊ mice compared with WT mice, showed more liver damage, higher mortality, and ineffective CO rescue in sepsis. Nfe2l2 ؊/؊ mice in sepsis also generated higher hepatic TNF-␣ mRNA levels, lower NRF-1 and PGC-1␣ mRNA levels, and no enhancement of anti-inflammatory Il10, Socs3, or bcl-x L gene expression. These findings disclose a highly structured transcriptional network that couples mitochondrial biogenesis to counter-inflammation with major implications for immune suppression in sepsis.Early survivors of severe sepsis often develop immune suppression (1, 2) and may later die with the multiple organ dysfunction syndrome (3). A key effector of multiple organ dysfunction syndrome is the liver, which is integral to the host response, especially in infections that activate Toll-like receptor 4 and NF-〉-dependent cytokine synthesis (4). The persistence of inflammatory cytokines such as TNF-␣ and IL-1␤ perpetuates immune activation, causing tissue damage and remodeling (5) and leads to sustained production of anti-inflammatory modulators and suppressors of adaptive immunity (6, 7).These anti-inflammatory modulators include the type II cytokine IL-10, the soluble IL-1 receptor antagonist (sIL-1Ra) 2 (5), and SOCS (suppressor of cytokine signaling) proteins (8). IL-10 is widely expressed in the liver (9, 10) by Kupffer cells (11), stellate cells (12), and hepatocytes (13), where it contributes to LPS tolerance (14). The IL-10 receptor activates JAK/STAT (Janus kinase/signal transducer and activator of transcription) to block the production of TNF-␣ and other NF-〉-dependent mediators (15), the basis for its anti-inflammatory effects (16). IL-10 also suppresses mononuclear cell function (17), and IL-10 secretion by macrophages and neutrophils negatively regulates the respon...

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Bcl-2 and Bcl-XL Regulate Proinflammatory Caspase-1 Activation by Interaction with NALP1

Cited by 295 publications

References 32 publications

Vaccinia Virus Protein F1L Is a Caspase-9 Inhibitor

Vaccinia Virus Protein F1L Is a Caspase-9 Inhibitor

AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

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