Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of neuraminidase, a viral enzyme that cleaves alpha ketosidic cell-bound sialic acids, to see if it accounts for parainfluenza and influenza virus-induced airway hyperreactivity. Accordingly, Vibrio cholerae neuraminidase was administered intratracheally in guinea pigs, and airway reactivity was assessed 3 h later. Removal of sialic acid residues was evaluated by histologic studies. Airway responsiveness was determined in anesthetized, tracheotomized, and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized bronchoconstrictor agents. Respiratory system conductance was measured by the occlusion method. Neuraminidase injected intratracheally did not change airway reactivity to 10(-4) to 10(-2) M acetylcholine or 10(-4) to 2.5 x 10(-3) M histamine; nor did it prevent aerosolized albuterol from inhibiting histamine-induced bronchoconstriction. Substance P (10(-6) to 5 x 10(-5) M) had no significant bronchoconstrictor effect on guinea pigs pretreated with saline or neuraminidase. In guinea pigs pretreated with aerosols of the neutral endopeptidase inhibitor phosphoramidon (10(-4) M) before the concentration curve to aerosolized substance P was recorded, neuraminidase significantly reduced substance P-induced bronchoconstriction. When bronchoconstriction was induced by the 4-11 fragment of substance P (10(-5) to 10(-2) M), which is devoid of positive charges, it did not differ significantly in guinea pigs pretreated with saline and those pretreated with neuraminidase. These results indicate that in the guinea pig, neuraminidase injected intratracheally does not induce non-specific airway hyperreactivity and may alter the binding of substance P to its receptors.
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PMID:Effects of neuraminidase on airway reactivity in the guinea pig. 137 96

Viral infection increases the airway smooth muscle response to substance P. This effect is due to decreased activity of neutral endopeptidase (EC 3.4.24.11), an enzyme that degrades substance P. Inhibition of neutral endopeptidase activity also potentiates substance P-induced 35SO4-labeled macromolecule secretion. Therefore we examined the in vitro effects of substance P on 35SO4-macromolecule secretion from the tracheae of influenza-infected ferrets. Despite a virus-induced loss of neutral endopeptidase activity (demonstrated in muscle bath experiments), there was no difference between control and infected tracheae in either baseline secretion [697 +/- 125 vs. 579 +/- 67 (SE) cpm/15 min; n = 15 tissues) or in the response to 10(-6) M substance P (increased by 218 +/- 63 and 195 +/- 51, respectively) or 10(-5) M substance P (increased by 416 +/- 95 and 354 +/- 54, respectively). Although phosphoramidon (10(-6) M) potentiated the secretory response to substance P, there was again no difference between control and infected tracheae. These data show that although viral infection decreases airway neutral endopeptidase activity, virus-induced hypersecretion is not due to a resulting increase in the secretory response to substance P.
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PMID:Viral infection increases contractile but not secretory responses to substance P in ferret trachea. 137 30

Ferret tracheal segments were infected with human influenza virus A/Taiwan/86 (H1N1) in vitro. After 4 days, the smooth muscle contractile responses to acetylcholine and to substance P were measured. The response to substance P was markedly accentuated, with a threefold increase in force of contraction at a substance P concentration of 10(-5) M, the highest concentration tested. In contrast, the response to acetylcholine was not affected by viral infection. Histological examination of tissues revealed extensive epithelial desquamation. Activity of enkephalinase (neutral metallo-endopeptidase, EC.3.4.24.11), an enzyme that degrades substance P, was decreased by 50% in infected tissues. Inhibiting enkephalinase activity by pretreating with thiorphan (10(-5) M) increased the response to substance P to the same final level in both infected and control tissues. Inhibiting other substance P-degrading enzymes including kininase II (angiotensin-converting enzyme), serine proteases, and aminopeptidases did not affect the response to substance P. Inhibiting cyclooxygenase and lipoxygenase activity using indomethacin and BW 755c did not affect hyperresponsiveness to substance P. Pretreating tissues with antagonists of alpha-adrenoceptors, beta-adrenoceptors, and H1 histamine receptors (phentolamine 10(-5) M, propranolol 5 X 10(-6) M, and pyrilamine 10(-5) M, respectively) had no effect on substance P-induced contraction. These results demonstrate that infection of ferret airway tissues with influenza virus increases the contractile response of airway smooth muscle to substance P. This effect is caused by decreased enkephalinase activity in infected tissues.
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PMID:Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. 304 36

Proteolytic cleavage of influenza virus hemagglutinin (HA) glycoprotein into subunits designated HA1 and HA2 is required for penetration of virus into the cell. It is generally assumed that this cleavage is an intracellular function of the host cell. Human adenoid fibroblast (HAF) lines, which support the growth of influenza A virus but release virus with an uncleaved HA, provide a model system that has allowed exploration of mechanisms of cleavage in vivo. Exposure of HAF-grown influenza virus to nasal secretions from children with respiratory tract symptoms induced HA cleavage and rendered virus fully infectious. Characterization of this proteolytic enzyme, present in the extracellular environment of the respiratory tract, suggests that it is a serine endopeptidase.
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PMID:Role of respiratory tract proteases in infectivity of influenza A virus. 354 17

Nuclear import and export of viral nucleic acids is crucial for the replication cycle of many viruses, and elucidation of the mechanism of these steps may provide a paradigm for understanding general biological processes. Influenza virus replicates its RNA genome in the nucleus of infected cells. The influenza virus NS2 protein, which had no previously assigned function, was shown to mediate the nuclear export of virion RNAs by acting as an adaptor between viral ribonucleoprotein complexes and the nuclear export machinery of the cell. A functional domain on the NS2 with characteristics of a nuclear export signal was mapped: it interacts with cellular nucleoporins, can functionally replace the effector domain of the human immunodeficiency virus type 1 (HIV-1) Rev protein and mediates rapid nuclear export when cross-linked to a reporter protein. Microinjection of anti-NS2 antibodies into infected cells inhibited nuclear export of viral ribonucleoproteins, suggesting that the Rev-like NS2 mediates this process. Therefore, we have renamed this Rev-like factor the influenza virus nuclear export protein or NEP. We propose a model by which NEP acts as a protein adaptor molecule bridging viral ribonucleoproteins and the nuclear pore complex.
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PMID:The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. 942 62

Influenza A viruses are important worldwide pathogens in humans and different animal species. The functions of most of the ten different viral proteins of this negative-strand RNA virus have been well elucidated. However, little is known about the virus-induced intracellular signalling events that support viral replication. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation and survival. Investigation of the function of this pathway has been facilitated by the identification of specific inhibitors such as U0126, which blocks the cascade at the level of MAPK/ERK kinase (MEK). Here we show that infection of cells with influenza A virus leads to biphasic activation of the Raf/MEK/ERK cascade. Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production. Thus, signalling through the mitogenic cascade seems to be essential for virus production and RNP export from the nucleus during the viral life cycle.
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PMID:Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. 1123 81

The influenza A virus NEP (NS2) protein is an structural component of the viral particle. To investigate whether this protein has an effect on viral RNA synthesis, we examined the expression of an influenza A virus-like chloramphenicol acetyltransferase (CAT) RNA in cells synthesizing the four influenza A virus core proteins (nucleoprotein, PB1, PB2, and PA) and NEP from recombinant plasmids. Influenza A virus NEP inhibited drastically, and in a dose-dependent manner, the level of CAT expression mediated by the recombinant influenza A virus polymerase. This inhibitory effect was not observed in an analogous artificial system in which expression of a synthetic CAT RNA is mediated by the core proteins of an influenza B virus. This result ruled out the possibility that inhibition of reporter gene expression was due to a general toxic effect induced by NEP. Analysis of the virus-specific RNA species that accumulated in cells expressing the type A recombinant core proteins and NEP showed that there was an important reduction in the levels of minireplicon-derived vRNA, cRNA, and mRNA molecules. Taken together, the results obtained suggest a regulatory role for NEP during virus-specific RNA synthesis, and this finding is discussed regarding the biological implications for the virus life cycle.
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PMID:Influenza A virus NEP (NS2 protein) downregulates RNA synthesis of model template RNAs. 1131 64

Nucleocytoplasmic transport of viral ribonucleoproteins (vRNPs) is an essential aspect of the replication cycle for influenza A, B, and C viruses. These viruses replicate and transcribe their genomes in the nuclei of infected cells. During the late stages of infection, vRNPs must be exported from the nucleus to the cytoplasm prior to transport to viral assembly sites on the cellular plasma membrane. Previously, we demonstrated that the influenza A virus nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs. In this report, we suggest that for influenza B and C viruses the nuclear export function is also performed by the orthologous NEP proteins (formerly referred to as the NS2 protein). The influenza virus B and C NEP proteins interact in the yeast two-hybrid assay with a subset of nucleoporins and with the Crm1 nuclear export factor and can functionally replace the effector domain from the human immunodeficiency virus type 1 Rev protein. We established a plasmid transfection system for the generation of virus-like particles (VLPs) in which a functional viral RNA-like chloramphenicol acetyltransferase (CAT) gene is delivered to a new cell. VLPs generated in the absence of the influenza B virus NEP protein were unable to transfer the viral RNA-like CAT gene to a new cell. From these data, we suggest that the nuclear export of the influenza B and C vRNPs are mediated through interaction between NEP proteins and the cellular nucleocytoplasmic export machinery.
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PMID:Influenza B and C virus NEP (NS2) proteins possess nuclear export activities. 1146 9

The cellular nuclear transport machinery relies on the assembly of specialized transport complexes between soluble transport receptors, transport substrates, and additional accessory proteins. This study focuses on the structural characteristics of influenza virus protein NS2 (NEP), which interacts with the nuclear export machinery during viral replication, and has been proposed to act as an adapter molecule between the nuclear export machinery and the viral ribonucleoprotein complex. For this purpose, we have purified recombinant NS2 under nondenaturing conditions, and have investigated its structure and aggregation state using optical spectroscopy, differential scanning calorimetry, as well as hydrodynamic techniques. Our results indicate that isolated NS2 exists as a monomer in solution, and adopts a compact, but very flexible conformation, which shows characteristics of the molten globule state under near physiological conditions. Proteolytic sensitivity suggests that, despite its overall plasticity, the structure of NS2 is heterogeneous. While the C terminus of the protein adopts a relatively rigid conformation, its N terminus, which is recognized by the nuclear export machinery, exists in a highly mobile and exposed state. It is proposed that the flexibility observed in the nuclear export domain of NS2 is an important element in the recognition of substrate proteins by the nuclear export machinery.
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PMID:Structural plasticity in influenza virus protein NS2 (NEP). 1175 4

The development of plasmid-based rescue systems for influenza virus has allowed previous studies of the neuraminidase (NA) virion RNA (vRNA) promoter to be extended, in order to test the hypothesis that alternative base pairs in the conserved influenza virus vRNA promoter cause attenuation when introduced into other gene segments. Influenza A/WSN/33 viruses with alternative base pairs in the duplex region of the vRNA promoter of either the polymerase acidic (PA) or the NS (non-structural 1, NS1, and nuclear export, NEP, -encoding) gene have been rescued. Virus growth in MDBK cells demonstrated that one of the mutations, the D2 mutation (U-A replacing G-C at nucleotide positions 12'-11), caused significant virus attenuation when introduced into either the PA or the NS gene. The D2 mutation resulted in the reduction of PA- or NS-specific vRNA and mRNA levels in PA- or NS-recombinant viruses, respectively. Since the D2 mutation attenuates influenza virus when introduced into either the PA or the NS gene segments, or the NA gene segment, as demonstrated previously, this suggests that this mutation will lead to virus attenuation when introduced into any of the eight gene segments. Such a mutation may be useful in the production of live-attenuated viruses.
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PMID:Alternative base pairs attenuate influenza A virus when introduced into the duplex region of the conserved viral RNA promoter of either the NS or the PA gene. 1260


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