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F Martinon

Publications and source records attributed to F Martinon.

At least 19 recordsLinked to original sources
PubMed2006

Inflammatory caspases and inflammasomes: master switches of inflammation.

Fifteen years have passed since the cloning and characterization of the interleukin-1beta-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.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.

Bcl10, a caspase recruitment domain (CARD)-containing protein identified from a breakpoint in mucosa-associated lymphoid tissue (MALT) B lymphomas, is essential for antigen-receptor-mediated nuclear factor kappaB (NF-kappaB) activation in lymphocytes. We have identified a novel CARD-containing protein and interaction partner of Bcl10, named Carma1. Carma1 is predominantly expressed in lymphocytes and represents a new member of the membrane-associated guanylate kinase family. Carma1 binds Bcl10 via its CARD motif and induces translocation of Bcl10 from the cytoplasm into perinuclear structures. Moreover, expression of Carma1 induces phosphorylation of Bcl10 and activation of the transcription factor NF-kappaB. We propose that Carma1 is a crucial component of a novel Bcl10-dependent signaling pathway in T-cells that leads to the activation of NF-kappaB.

Amino Acid Sequence↗
PubMed2001

Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension.

The Bcl-2 family of proteins plays a central regulatory role in apoptosis. We have identified a novel, widely expressed Bcl-2 member which we have named Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apoptotic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4. Unlike Bcl-2, however, the C-terminal membrane anchor region is preceded by a unique 250 amino acid insertion containing two tandem repeats. No interaction of Bcl-rambo with either anti-apoptotic (Bcl-2, Bcl-x(L), Bcl-w, A1, MCL-1, E1B-19K, and BHRF1) or pro-apoptotic (Bax, Bak, Bik, Bid, Bim, and Bad) members of the Bcl-2 family was observed. In mammalian cells, Bcl-rambo was localized to mitochondria, and its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. Surprisingly, the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain and not by the Bcl-2 homology region. Thus, Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.

Amino Acid Motifs↗
PubMed2001

Equine herpesvirus protein E10 induces membrane recruitment and phosphorylation of its cellular homologue, bcl-10.

v-E10, a caspase recruitment domain (CARD)-containing gene product of equine herpesvirus 2, is the viral homologue of the bcl-10 protein whose gene was found to be translocated in mucosa-associated lymphoid tissue (MALT) lymphomas. v-E10 efficiently activates the c-jun NH(2)-terminal kinase (JNK), p38 stress kinase, and the nuclear factor (NF)-kappaB transcriptional pathway and interacts with its cellular homologue, bcl-10, via a CARD-mediated interaction. Here we demonstrate that v-E10 contains a COOH-terminal geranylgeranylation consensus site which is responsible for its plasma membrane localization. Expression of v-E10 induces hyperphosphorylation and redistribution of bcl-10 from the cytoplasm to the plasma membrane, a process which is dependent on the intactness of the v-E10 CARD motif. Both membrane localization and a functional CARD motif are important for v-E10-mediated NF-kappaB induction, but not for JNK activation, which instead requires a functional v-E10 binding site for tumor necrosis factor receptor-associated factor (TRAF)6. Moreover, v-E10-induced NF-kappaB activation is inhibited by a dominant negative version of the bcl-10 binding protein TRAF1, suggesting that v-E10-induced membrane recruitment of cellular bcl-10 induces constitutive TRAF-mediated NF-kappaB activation.

Adaptor Proteins, Signal Transducing↗
PubMed2001

DNA vaccination of macaques with several different Nef sequences induces multispecific T cell responses.

CD8(+) T lymphocytes play a key role in controlling viremia during primary human immunodeficiency virus-1 and in maintaining disease-free infection. It has recently been shown that DNA immunization of rhesus monkeys can elicit strong, long-lived antigen-specific cytotoxic T lymphocyte (CTL) responses. In previous work, it was shown that macaque CTL responses to lipopeptide vaccination were directed against a limited number of epitopes. In the present study, we used the DNA immunization approach to enlarge T cell responses to several epitopes and to multiple isolates. We immunized macaques with a mixture of six plasmids reflecting the variability of Nef epitopic regions in the simian immunodeficiency virus (SIV) mac251 primary isolate. The Nef genes from viruses included in the SIVmac251 primary isolate were sequenced and the six selected sequences were individually subcloned into the pCI vector, under cytomegalovirus enhancer/promoter control, and injected into macaques. We show that DNA immunization with Nef sequences induced interferon-gamma (IFN-gamma) secreting cell responses directed against several regions of Nef. Reacting T cell lines were expanded in vitro and multispecific CTL responses mapping the 96-138 Nef region were analyzed. Several peptides recognized by CTL were identified and studies using peptides reflecting the variability of Nef indicated that all of the Nef variants were recognized in the 96-138 region. Moreover, CTL responses were directed against an immunodominant epitope located in a functional region within the Nef protein that is essential for viral replication. This work shows that our approach of DNA immunization with several sequences induced multispecific T cell responses recognizing variants included in the SIVmac251 primary isolate.

Amino Acid Sequence↗
PubMed2000

Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2.

Adenovirus encodes multiple gene products that regulate proapoptotic cellular responses to viral infection mediated by both the innate and adaptive immune systems. The E3-10.4K and 14.5K gene products are known to modulate the death receptor Fas. In this study, we demonstrate that an additional viral E3 protein, 6.7K, functions in the specific modulation of the two death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The 6.7K protein is expressed on the cell surface and forms a complex with the 10.4K and 14.5K proteins, and this complex is sufficient to induce down-modulation of TRAIL receptor-1 and -2 from the cell surface and reverse the sensitivity of infected cells to TRAIL-mediated apoptosis. Down-modulation of TRAIL-R2 by the E3 complex is dependent on the cytoplasmic tail of the receptor, but the death domain alone is not sufficient. These results identify a mechanism for viral modulation of TRAIL receptor-mediated apoptosis and suggest the E3 protein complex has evolved to regulate the signaling of selected cytokine receptors.

Adenoviridae↗
PubMed2000

The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.

BACKGROUND: Activation of Fas (CD95) by its ligand (FasL) rapidly induces cell death through recruitment and activation of caspase-8 via the adaptor protein Fas-associated death domain protein (FADD). However, Fas signals do not always result in apoptosis but can also trigger a pathway that leads to proliferation. We investigated the level at which the two conflicting Fas signals diverge and the protein(s) that are implicated in switching the response. RESULTS: Under conditions in which proliferation of CD3-activated human T lymphocytes is increased by recombinant FasL, there was activation of the transcription factors NF-kappaB and AP-1 and recruitment of the caspase-8 inhibitor and FADD-interacting protein FLIP (FLICE-like inhibitory protein). Fas-recruited FLIP interacts with TNF-receptor associated factors 1 and 2, as well as with the kinases RIP and Raf-1, resulting in the activation of the NF-kappaB and extracellular signal regulated kinase (Erk) signaling pathways. In T cells these two signal pathways are critical for interleukin-2 production. Increased expression of FLIP in T cells resulted in increased production of interleukin-2. CONCLUSIONS: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.

Apoptosis↗
PubMed2000

Activation of a pro-apoptotic amplification loop through inhibition of NF-kappaB-dependent survival signals by caspase-mediated inactivation of RIP.

Death domain containing members of the tumor necrosis factor receptor (TNFR) superfamily can induce apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. Frequently, NF-kappaB activation conveys protection against cell death. We show that the serine/threonine kinase RIP that is required for TNF-induced NF-kappaB activation is processed by caspase-8 into a dominant-negative (DN) fragment during death receptor-induced apoptosis, thereby leading to a blockade of NF-kappaB-mediated anti-apoptotic signals. Our results suggest that cleavage of RIP is part of an amplification loop which is triggered by Fas and most likely by other death receptors.

Amino Acid Sequence↗
PubMed2000

Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.

Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-kappaB and AP-1. Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1beta treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2000

DNA vaccine protection against challenge with simian/human immunodeficiency virus 89.6 in rhesus macaques.

Twelve Rhesus macaques were immunized by intramuscular injection of naked DNA encoding the SlVmac gag and nef genes, HIV-1 89.6 env and rev genes and the simian interleukin-12 (IL-12) gene. Six of the animals also received two intramuscular injections of gp140 89.6 formulated in QS21. The monkeys were challenged by the intrarectal route, in parallel with six control monkeys, using 750 TCID50 of SHIV-89.6. Virus recovery in PBMC by co-cultivation was as follows: controls: six out of six; DNA only: five out of six; DNA + protein: two out of six. The five animals that remained virus free after this first challenge were challenged a second time, again by the intrarectal route and in parallel with four naive controls, using 600 TCID50 of pathogenic SHIV-89.6P. A rapid CD4 cell count decline was observed in the four control monkeys as well as in the monkey vaccinated with DNA only, but in none of the four animals immunized with DNA + protein. No virus was recovered from PBMC in two of these monkeys, and viral RNA loads in plasma were greatly reduced in three of them as compared with the controls. Absence of virus in PBMC was ascertained by whole blood transfusion to naive recipients. Altogether, this shows that the DNA prime-protein boost vaccine regimen could provide some protection against mucosal SHIV infection in rhesus monkeys, whereas DNA alone was ineffective.

AIDS Vaccines↗
PubMed1999

Degradation of ZAP-70 following antigenic stimulation in human T lymphocytes: role of calpain proteolytic pathway.

T cell activation by the specific Ag results in dramatic changes of the T cell phenotype that include a rapid and profound down-regulation and degradation of triggered TCRs. In this work, we investigated the fate of the TCR-associated ZAP-70 kinase in Ag-stimulated T cells. T cells stimulated by peptide-pulsed APCs undergo an Ag dose-dependent decrease of the total cellular content of ZAP-70, as detected by FACS analysis and confocal microscopy on fixed and permeabilized T cell-APC conjugates and by Western blot on total cell lysates. The time course of ZAP-70 consumption overlaps with that of zeta-chain degradation, indicating that ZAP-70 is degraded in parallel with TCR internalization and degradation. Pharmacological activation of protein kinase C (PKC) does not induce ZAP-70 degradation, which, on the contrary, requires activation of protein tyrosine kinases. Two lines of evidence indicate that the Ca2+-dependent cysteine protease calpain plays a major role in initiating ZAP-70 degradation: 1) treatment of T cells with cell-permeating inhibitors of calpain markedly reduces ZAP-70 degradation; 2) ZAP-70 is cleaved in vitro by calpain. Our results show that, in the course of T cell-APC cognate interaction, ZAP-70 is rapidly degraded via a calpain-dependent mechanism.

Antigen-Presenting Cells↗
PubMed1999

Apoptosis: Silencing the death receptors.

Spontaneous signaling from death-domain-containing receptors can result in inappropriate cell death. An inhibitory protein has recently been identified, called silencer of death domains (SODD), that binds to the death domain of tumor necrosis factor receptor 1, thereby negatively regulating downstream signaling.

Amino Acid Sequence↗
PubMed1999

Equine herpesvirus-2 E10 gene product, but not its cellular homologue, activates NF-kappaB transcription factor and c-Jun N-terminal kinase.

We have previously reported on the death effector domain containing E8 gene product from equine herpesvirus-2, designated FLICE inhibitory protein (v-FLIP), and on its cellular homologue, c-FLIP, which inhibit the activation of caspase-8 by death receptors. Here we report on the structure and function of the E10 gene product of equine herpesvirus-2, designated v-CARMEN, and on its cellular homologue, c-CARMEN, which contain a caspase-recruiting domain (CARD) motif. c-CARMEN is highly homologous to the viral protein in its N-terminal CARD motif but differs in its C-terminal extension. v-CARMEN and c-CARMEN interact directly in a CARD-dependent manner yet reveal different binding specificities toward members of the tumor necrosis factor receptor-associated factor (TRAF) family. v-CARMEN binds to TRAF6 and weakly to TRAF3 and, upon overexpression, potently induces the c-Jun N-terminal kinase (JNK), p38, and nuclear factor (NF)-kappaB transcriptional pathways. c-CARMEN or truncated versions thereof do not appear to induce JNK and NF-kappaB activation by themselves, nor do they affect the JNK and NF-kappaB activating potential of v-CARMEN. Thus, in contrast to the cellular homologue, v-CARMEN may have additional properties in its unique C terminus that allow for an autonomous activator effect on NF-kappaB and JNK. Through activation of NF-kappaB, v-CARMEN may regulate the expression of the cellular and viral genes important for viral replication.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Persistent alterations in T-cell repertoire, cytokine and chemokine receptor gene expression after 1 year of highly active antiretroviral therapy.

OBJECTIVES: To examine T-cell repertoire modifications, the evolution of T-helper (TH)1/TH2 cytokine imbalance and modifications in chemokine receptor expression when the viral load is decreased by 2-3 log10 copies/ml under highly active antiretroviral therapy (HAART). DESIGN: Sixteen patients previously treated with zidovudine and lamivudine, with CD4 cells below 300 x 10(6)/l and viraemia above 30000 copies/ml were treated by saquinavir and ritonavir together with both reverse transcriptase (RT) inhibitors (ANRS 069 trial). T-cell repertoire, chemokine receptor and lymphokine expression were studied from peripheral blood mononuclear cells sampled at weeks 0, 24 and 48. METHODS: T-cell repertoire study was carried out using the Immunoscope method. Interleukin (IL)-12 receptor beta2, CC-chemokine receptor (CCR)-3, CXC-chemokine receptor-4 and CCR-5 expression in CD4+ cells was measured by kinetic quantitative PCR and IL-2, IL-4, IL-10, IL-13, interferon (IFN)-gamma were measured using a quantitative RT-PCR assay with homologous internal standards. RESULTS: Repertoire alterations were more frequent in CD4- than in CD4+ cells and persisted despite undetectable viraemia. Increased CCR-3 expression and spontaneous IFN-gamma as well as mitogenic induced IL-13 were observed at baseline and decreased slightly under HAART. CONCLUSION: The CD8+ cell repertoire alterations were profound, whereas the CD4+ cell alterations were moderate and both persisted unchanged under HAART. The TH1/TH2 imbalance was more related to TH2 over-expression than to TH1 deficiency and persisted for at least 1 year under HAART.

Adult↗
PubMed1998

Identification of CARDIAK, a RIP-like kinase that associates with caspase-1.

Members of the tumor necrosis factor receptor (TNFR) superfamily have an important role in the induction of cellular signals resulting in cell growth, differentiation and death. TNFR-1 recruits and assembles a signaling complex containing a number of death domain (DD)-containing proteins, including the adaptor protein TRADD and the serine/threonine kinase RIP, which mediates TNF-induced NF-kappa B activation. RIP also recruits caspase-2 to the TNFR-1 signaling complex via the adaptor protein RAIDD, which contains a DD and a caspase-recruiting domain (CARD). Here, we have identified a RIP-like kinase, termed CARDIAK (for CARD-containing interleukin (IL)-1 beta converting enzyme (ICE) associated kinase), which contains a serine/threonine kinase domain and a carboxy-terminal CARD. Overexpression of CARDIAK induced the activation of both NF-kappa B and Jun N-terminal kinase (JNK). CARDIAK interacted with the TNFR-associated factors TRAF-1 and TRAF-2, and a dominant-negative form of TRAF-2 inhibited CARDIAK-induced NF-kappa B activation. Interestingly, CARDIAK specifically interacted with the CARD of caspase-1 (previously known as ICE), and this interaction correlated with the processing of pro-caspase-1 and the formation of the active p20 subunit of caspase-1. Together, these data suggest that CARDIAK may be involved in NF-kappa B/JNK signaling and in the generation of the proinflammatory cytokine IL-1 beta through activation of caspase-1.

Amino Acid Sequence↗
PubMed1998

Adjuvant is required when using Env lipopeptide construct to induce HIV type 1-specific neutralizing antibody responses in mice in vivo.

Extensive immunological studies on HIV-1 infection, the causative agent of AIDS in humans, have led to the conclusion that efficient protection against this infection should require early elicitation of neutralizing antibodies as well as cellular immune and particularly cytotoxic T lymphocyte responses. The use of synthetic peptides modified at one end by introduction of a lipidic tail is now well known to be an effective means of eliciting virus-specific cytotoxic T lymphocyte responses in vivo, both in mouse and humans. To ascertain that such a strategy can be used for vaccinal purposes, particularly against HIV-1 infection, it remains to be determined whether these molecules can also act as effective inducers of antibody responses, most of all of the neutralizing type. The present study set out to address this question by using a synthetic HIV-1 ENV lipopeptide construct, previously identified as a potent immunogen for in vivo induction of ENV-specific CTL responses in BALB/c mice. We first showed that V3 peptide-specific antibodies were effectively induced by the lipopeptide construct. However, we provided evidence that the biological activity of these antibodies, i.e., their ability to neutralize HIV-1 infectivity in vitro, was strongly influenced by the immunizing conditions and protocol, in that only those antibodies generated by the use of adjuvanted lipopeptide formulations were effective. Albeit at a slightly lower efficacy than by the intraperitoneal route, neutralizing antibodies could also be induced using the subcutaneous route. With the prospect of a human peptide vaccine in mind, we then studied the properties of different known or possibly clinically relevant adjuvants. We found that alum, the only relevant adjuvant for human use, not only provides inefficient help to the lipopeptide construct in generating neutralizing antibodies, but tends to have deleterious effects on the ability of the construct to induce CTL responses. The only protocol that gave satisfactory results in terms of the magnitude of the neutralizing antibody responses was a mineral oil-based lipopeptide formulation. When induced under those conditions, strong neutralizing activities were still present up to 8 months after the last injection.

Adjuvants, Immunologic↗
PubMed1998

MyD88, an adapter protein involved in interleukin-1 signaling.

MyD88 has a modular organization, an N-terminal death domain (DD) related to the cytoplasmic signaling domains found in many members of the tumor necrosis factor receptor (TNF-R) superfamily, and a C-terminal Toll domain similar to that found in the expanding family of Toll/interleukin-1-like receptors (IL-1R). This dual domain structure, together with the following observations, supports a role for MyD88 as an adapter in IL-1 signal transduction; MyD88 forms homodimers in vivo through DD-DD and Toll-Toll interactions. Overexpression of MyD88 induces activation of the c-Jun N-terminal kinase (JNK) and the transcription factor NF-kappaB through its DD. A point mutation in MyD88, MyD88-lpr (F56N), which prevents dimerization of the DD, also blocks induction of these activities. MyD88-induced NF-kappaB activation is inhibited by the dominant negative versions of TRAF6 and IRAK, which also inhibit IL-1-induced NF-kappaB activation. Overexpression of MyD88-lpr or MyD88-Toll (expressing only the Toll domain) acted to inhibit IL-1-induced NF-kappaB and JNK activation in a 293 cell line overexpressing the IL-1RI. MyD88 coimmunoprecipitates with the IL-1R signaling complex in an IL-1-dependent manner.

Adaptor Proteins, Signal Transducing↗