The High Mobility Group protein HMG I(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene

Thanos, Dimitris; Maniatis, Tom

doi:10.1016/0092-8674(92)90554-p

Cited by 614 publications

(540 citation statements)

References 48 publications

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“…A Myc tag-encoding sequence was introduced at the 5Ј end of the PYPAF1 cDNA from these latter plasmids to generate pPYPAF1-wt_Myc, pPYPAF1-Arg554X_Myc, and pPYPAF1-Arg260Trp_Myc. The NF-B p65 expression plasmid has been described previously (19).…”

Section: Methodsmentioning

confidence: 99%

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

Jéru

Hayrapetyan

Duquesnoy

et al. 2006

Arthritis & Rheumatism

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Objective. To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes.Methods. The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-B signaling was subsequently assessed.Results. No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-B proinflammatory pathways, and that the identified nonsense mutation impaired this property.Conclusion. These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-B signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient.

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Section: Methodsmentioning

confidence: 99%

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

Jéru

Hayrapetyan

Duquesnoy

et al. 2006

Arthritis & Rheumatism

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“…Inhibition of PI3K activity enhances poly(I:C)-and LPS-mediated NF-jB but not IRF3 activation in DC IFN-b gene expression requires cooperation between NF-jB [28,29] and IRF3 [30][31][32] transcription factors. Therefore, we quantified the levels of NF-jB and IRF3 DNA-binding activities in nuclear extracts from wortmannin-treated DC versus control counterparts following LPS or poly(I:C) stimulation.…”

Section: Pi3k Inhibition Enhances Ifn-b Synthesis In DC Stimulated Bymentioning

confidence: 97%

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

Aksoy

Berghe²,

Detienne

et al. 2005

Eur. J. Immunol.

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Phosphoinositide 3-kinases (PI3K) are known to regulate Toll-like receptor (TLR)-mediated inflammatory responses, but their impact on the different pathways of TLR signaling remains to be clarified. Here, we investigated the consequences of pharmacological inhibition of PI3K on Toll-IL-1 receptor domain-containing adapterinducing IFN-b (TRIF)-dependent signaling, which induces IFN-b gene expression downstream of TLR3 and TLR4. First, treatment of monocyte-derived dendritic cells (DC) with wortmannin or LY294002 was found to enhance IFN-b expression upon TLR3 or TLR4 engagement. In the same models of DC activation, PI3K inhibition increased DNA-binding activity of NF-jB, but not interferon response factor (IRF)-3, the key transcription factors required for TLR-mediated IFN-b synthesis. In parallel, wortmannin-treated DC exhibited enhanced levels of IjB kinase (IKK)-a/b phosphorylation and IjB-a degradation with a concomitant increase in NF-jB nuclear translocation. Experiments carried out in HEK 293T cells stably expressing TLR3 or TLR4 confirmed that inhibition of PI3K activity enhances NF-jB-dependent promoters as well as IFN-b promoter activities without interfering with transcription at the positive regulatory domain III-I. Furthermore, wortmannin enhanced NF-jB activity induced by TRIF overexpression in HEK 293T cells, while overexpression of catalytically active PI3K selectively attenuated TRIF-mediated NF-jB transcriptional activity. Finally, in coimmunoprecipitation experiments, we showed that PI3K physically interacted with TRIF. We conclude that inhibition of PI3K activity enhances TRIF-dependent NF-jB activity, and thereby increases IFN-b synthesis elicited by TLR3 or TLR4 ligands.

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“…5A). Upon addition, however, of the DNA dodecamer comprising the PRDII region of the interferon+ gene enhancer (Thanos & Maniatis, 1992; Fig. 5B).…”

Section: Jr Huth Et Almentioning

confidence: 99%

Design of an expression system for detecting folded protein domains and mapping macromolecular interactions by NMR

et al. 1997

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Two protein expression vectors have been designed for the preparation of NMR samples. The vectors encode the immunoglobulin-binding domain of streptococcal protein G (GB1 domain) linked to the N-terminus of the desired proteins. This fusion strategy takes advantage of the small size, stable fold, and high bacterial expression capability of the GB 1 domain to allow direct NMR spectroscopic analysis of the fusion protein by ' H-l5N correlation spectroscopy.Using this system accelerates the initial assessment of protein NMR projects such that, in a matter of days, the solubility and stability of a protein can be determined. In addition, "N-labeling of peptides and their testing for DNA binding are facilitated. Several examples are presented that demonstrate the usefulness of this technique for screening protein/DNA complexes, as well as for probing ligand-receptor interactions, using iSN-labeled GBI-peptide fusions and unlabeled target.Keywords: domain structure; GBI-fusion protein; intermolecular interactions; NMR When investigating whether a protein or protein-DNA complex is suitable for NMR structural analysis, several technical goals must be met. First, the size, solubility, and stability of the protein domain must be optimized. Second, the protein should be expressed in a host (usually bacteria), allowing for easy and inexpensive labeling with "C and "N. A third challenge pertains to the preparation of protein-DNA complexes where both the protein and DNA sequences must be optimized to achieve a complex that is most amenable to structural investigation; that is, the system should not exhibit intermediate exchange on the NMR time scale. The practical size limit for structure determination by current solution NMR methodology is approximately 40 kDa, so that, for many proteins, subcloning of a smaller domain that retains functional qualities of the full-length protein is required. All too frequently, however, engineering of protein domains results in limited solubility and/or low stability, often to the point where many engineered proteins are partially or predominately unfolded. In practice, many variations of a protein sequence may be evaluated by NMR

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The High Mobility Group protein HMG I(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene

Cited by 614 publications

References 48 publications

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

Design of an expression system for detecting folded protein domains and mapping macromolecular interactions by NMR

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