Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dengue virus nonstructural protein 1 (NS1) is expressed on the surface of infected cells and is a target of human antibody responses to dengue virus infection. We show here that dengue virus uses the cellular glycosyl-phosphatidylinositol (GPI) linkage pathway to express a GPI-anchored form of NS1 and that GPI anchoring imparts a capacity for signal transduction in response to binding of NS1-specific antibody. This study is the first to identify GPI linkage of a virus-encoded protein. The GPI anchor addition signal for NS1 was identified, by transfection of HeLa cells with dengue cDNA constructs, as a downstream hydrophobic domain in NS2A. GPI linkage of NS1 in both transfected and infected cells was demonstrated by cleavage of NS1 from the surface by PI-specific phospholipase C and by metabolic incorporation of the GPI-specific components ethanolamine and inositol. In common with other GPI-anchored proteins, addition of specific antibody resulted in signal transduction, as evidenced by tyrosine phosphorylation of cellular proteins. Antibody-induced signal transduction by GPI-linked NS1 suggests a mechanism of cellular activation that may contribute to the pathogenesis of human dengue disease. Signal transduction by a GPI-anchored viral antigen interacting with a specific antibody that it induces is a new concept in the pathogenesis of viral disease.
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PMID:Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. 1092 95

Dengue virus NS1 is a viral nonstructural protein detected in sera of infected individuals and in infected cells. Multiple NS1 structural forms have been reported but the functional characteristics of these forms remain unknown. In this study, a set of 293T cell lines stably expressing recombinant dengue NS1 without additional C-terminal sequence (rNS1s), with a heterologous transmembrane segment (rNS1tm), or with the 26-residue N-terminal portion of NS2A (rNS1v1) was established to aid in the characterization of different NS1 forms. Each NS1 protein form had distinct phenotypes and the following properties were documented: (1) dissipated expression in the cytoplasm, dimerization, and N-glycosylation were observed, regardless of the forms of NS1 expressed; (2) the rNS1v1 and rNS1tm forms, but not the rNS1s, were observed prominently on the surface membrane; (3) only the rNS1v1 form incorporated ethanolamine, a precursor of the glycosylphosphatidylinositol moiety, and was partially sensitive to digestion with phosphatidylinositol-specific phospholipase C. The stable 239T transfectants expressing multiple forms of dengue NS1 may be a useful model to investigate the function of NS1 and the mechanism by which NS1 associates with membrane.
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PMID:Characterization of dengue virus NS1 stably expressed in 293T cell lines. 1733 94

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS.
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PMID:Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome. 2944 78