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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells respond to treatment with interferons by synthesizing several induced proteins, including one or more structurally related proteins collectively called Mx. Nuclear and cytoplasmic forms of Mx have been described, some of which inhibit virus replication. Human MxA is a cytoplasmic protein that specifically inhibits the multiplication of influenza virus and vesicular stomatitis virus. Here, we describe a mutant MxA protein, MxA(R645), which inhibited influenza virus but was inactive against vesicular stomatitis virus. It differs from wild-type MxA by a Glu to Arg substitution near the carboxy terminus. Like wild-type MxA, and as expected for an Mx protein acting in the cytoplasm, MxA(R645) blocked influenza virus at a step after primary transcription. When moved to the nucleus of transfected cells with the help of a foreign nuclear transport signal, its mode of action changed. Like mouse Mx1, nuclear MxA(R645) interfered with primary transcription of influenza virus, which is a nuclear process. Our results thus define an MxA region that determines antiviral specificity and further demonstrate that nuclear forms of MxA can mimic the action of mouse Mx1 whose natural location is the cell nucleus.
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PMID:Mechanism of human MxA protein action: variants with changed antiviral properties. 131 72

The interferon-induced Mx1 protein of mice confers selective resistance to influenza virus. It inhibits viral mRNA synthesis in the nucleus of influenza virus-infected cells. The related human MxA protein is localized in the cytoplasm and can inhibit influenza virus and vesicular stomatitis virus but not other viruses. MxA blocks a poorly defined cytoplasmic multiplication step of influenza virus that follows primary transcription of the viral genome. We previously showed that nuclear variants of MxA that carry an artificial nuclear translocation signal were also active against influenza virus. However, these variants blocked primary transcription of influenza virus. In the present study, we addressed the question of whether cytoplasmic forms of Mx1 were capable of mimicking the antiviral action of MxA by determining the antiviral activities of mutant mouse Mx1 protein. Cytoplasmic Mx1(E614), which differs from wild-type Mx1 by a single amino acid substitution in its nuclear transport signal, failed to inhibit the multiplication of influenza virus and vesicular stomatitis virus. Relocation of Mx1(E614) to the nucleus with the help of the simian virus 40 large T nuclear translocation signal attached to its amino terminus restored the influenza virus-inhibiting activity. Other changes in the carboxy-terminal region of Mx1 also abolished transport to the nucleus and simultaneously abolished antiviral activity. One of these variants, Mx1/A, gained activity against influenza virus upon relocation to the nucleus. These results demonstrate that unlike human MxA, the mouse Mx1 protein can function only in the nucleus. This finding has important implications regarding the mechanistic details of Mx protein action.
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PMID:Nuclear localization of mouse Mx1 protein is necessary for inhibition of influenza virus. 132 Dec 88

The interferon-induced human MxA protein inhibits the multiplication of influenza virus and vesicular stomatitis virus (VSV) by an unknown mechanism. Here we show that MxA protein interferes with VSV mRNA synthesis. Transfected Swiss 3T3 mouse cells constitutively expressing MxA protein and control cells were infected with VSV, and viral RNA and protein synthesis was monitored. Viral macromolecules were very abundant in control cells at 4 h postinfection, whereas the pools of VSV proteins and RNAs were more than 50-fold reduced in cells expressing MxA. To determine whether MxA inhibited VSV primary transcription, we infected the cells in the presence of the protein synthesis inhibitor cycloheximide and measured the pools of the five viral mRNAs at 4 h postinfection. VSV L mRNA concentration was more than 20-fold reduced, VSV G mRNA concentration was about 10-fold reduced, and the other viral mRNAs were three- to fivefold less abundant in MxA-expressing cells than in control cells. Our results thus indicate that MxA interferes with normal VSV mRNA synthesis either directly by inhibiting the activity of the viral polymerase complex or indirectly by reducing the stability of the VSV mRNAs.
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PMID:Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein. 164 44

MxA and MxB are interferon-induced proteins of human cells and are related to the murine protein Mx1, which confers selective resistance to influenza virus. In contrast to the nuclear murine protein Mx1, MxA and MxB are located in the cytoplasm, and their role in the interferon-induced antiviral state was unknown. In this report we show that transfected cell lines expressing MxA acquired a high degree of resistance to influenza A virus. Surprisingly, MxA also conferred resistance to vesicular stomatitis virus. Expression of MxA in transfected 3T3 cells had no effect on the multiplication of two picornaviruses, a togavirus, or herpes simplex virus type 1. Treatment of MxA-expressing cells with antibodies to mouse alpha-beta interferon did not abolish the resistance phenotype. The conclusion that resistance to influenza virus and vesicular stomatitis virus was due to the specific action of MxA is further supported by the observation that transfected 3T3 cell lines expressing the related MxB failed to acquire virus resistance.
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PMID:Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. 216 46

The interferon-inducible gene (IFI-78K gene) that codes for a human protein, p78, of 78,000 Mr is the equivalent of the mouse Mx gene encoding Mx protein. The IFI-78K gene is located on chromosome 21 together with the alpha/beta interferon (IFN-alpha/beta) receptor. The p78 protein is important since it may be involved in resistance to influenza viruses. The regulation of the IFI-78K gene was studied in human diploid cells by using a cDNA probe to p78 mRNA and specific monoclonal antibodies to p78 protein. The IFI-78K gene, a normally quiescent gene, is transcriptionally regulated by IFN-alpha, and its induction does not require protein synthesis. The rate of transcription measured in a run-on assay increased rapidly but transiently. The level of p78 mRNA increased up to 8 h, declining slowly afterwards. The p78 protein, undetectable in untreated cells, accumulated up to 16 h, and its amount remained stable for at least 36 h after the addition of IFN-alpha. Cytokines such as tumor necrosis factor, interleukin-1 alpha, and interleukin-1 beta activated the IFI-78K gene at concentrations comparable to that of IFN-alpha. However, gene activation by these cytokines required protein synthesis. Poly(rI)-poly(rC) induced the IFI-78K gene directly at the transcriptional level without requirement for protein synthesis. Newcastle disease virus, influenza virus, and to a lesser extent vesicular stomatitis virus also induced the IFI-78K gene in the absence of any protein synthesis. Induction of transcription by viruses was markedly enhanced by pretreatment of cells with IFN-gamma (which by itself is a poor inducer of the IFI-78K gene), resulting in accumulation of p78 protein during the course of infection; this suggests that IFN-gamma programs cells to full antiviral activity upon virus infection.
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PMID:Regulation of the interferon-inducible IFI-78K gene, the human equivalent of the murine Mx gene, by interferons, double-stranded RNA, certain cytokines, and viruses. 254 74

Interferons induce a number of different proteins which mediate the antiproliferative, antiviral, and immunomodulatory functions of interferons. Interferon-induced Mx proteins, which confer resistance to influenza, vesicular stomatitis, and measles viruses, contain consensus GTPase sequence elements. Insect cell-produced purified murine Mx1 and human MxA proteins were found to hydrolyze GTP with Km = 65 microM (Vmax, 7.1 min-1) and 62 microM (Vmax, 3.1 min-1), respectively. The GTPase activity of Mx1 and MxA proteins was strictly dependent on Mg2+ ions. Murine Mx1 protein was inactivated at 10 degrees C lower temperatures than MxA protein. As analyzed, by filter binding assay, Mx1 protein (at 1 microM) showed a relatively high affinity for GDP (Kd = 1.0 x 10(-7) M) and approximately 340-fold lower affinity for guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) (Kd = 3.4 x 10(-5) M). The Kd values for MxA protein were 2.0 x 10(-7) M for GDP and 5.9 x 10(-6) M for GTP gamma S, showing approximately a 30-fold affinity difference. ATP, UTP, or CTP did not inhibit the Mx protein-dependent GTPase activity, suggesting that Mx1 and MxA proteins are highly specific for guanosine nucleotides. In conclusion recombinant nuclear murine Mx1 and cytoplasmic human MxA proteins show clear differences in their enzymatic activities and nucleotide binding characteristics. How these differences influence their cellular functions and antiviral potential is presently not known.
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PMID:Enzymatic characterization of interferon-induced antiviral GTPases murine Mx1 and human MxA proteins. 750 89

Mx proteins have molecular masses between 70 and 80 kDa and their synthesis is tightly regulated by interferons in mammalian and non-mammalian vertebrates. Some Mx proteins function as intracellular mediators of the interferon-induced antiviral state. When suitable cDNA constructs were constitutively expressed in mouse 3T3 cells the mouse nuclear Mx1 protein conferred selective resistance to influenza virus. The human cytoplasmic MxA protein conferred resistance to influenza virus and vesicular stomatitis virus but not to other viruses. Mx1 blocks influenza virus mRNA synthesis within the nucleus of infected cells. Mx1 presumably interacts with the influenza virus polymerase subunit PB2, because overexpression of PB2 titrates out the Mx1 block. MxA does not inhibit mRNA synthesis of influenza virus; it inhibits a subsequent cytoplasmic viral multiplication step. A possible target is the transport of newly synthesized influenza virus polymerase proteins back to the nucleus. Inhibition by MxA of vesicular stomatitis virus, which replicates in the cytoplasm, is at the transcriptional level. Parts of the N-terminal halves of all known Mx proteins are highly conserved. They contain the typical GTP-binding motif and show significant homology to other members of a new family of GTPases that includes rat dynamin, Drosophila Shibire and the yeast proteins Vps1/Spo15 and Mgm1. Purified Mx1 and MxA proteins possess GTPase activity. The GTP/GDP conversion rates are about 40 per min, and Km values about 700 microM. Mx1 and MxA variants with mutations in the GTP-binding sequences that violate the consensus are unable to confer virus resistance in vivo or to hydrolyse GTP in vitro, suggesting that GTPase activity is necessary for antiviral activity of Mx proteins. We hypothesize that the antivirally active Mx proteins (directly or indirectly) bind to polymerase proteins of susceptible viruses, thereby abolishing normal viral polymerase function. Interaction of Mx with viral targets is probably a GTP-dependent process.
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PMID:Mx proteins: GTPases involved in the interferon-induced antiviral state. 750 12

We have cloned a 2.4-kb cDNA containing the complete coding sequence of ovine Mx from a lambda ZAP library constructed using RNA from the endometrium of a normal sheep on day 16 of pregnancy. Ovine Mx shows 80% similarity to human MxA. Human and mouse Mx are type-1 interferon (IFN)-induced genes that have previously been shown to confer resistance to influenza virus. The ovine Mx cDNA contains an open reading frame of 1962 nucleotides (nt) coding for a 653-amino-acid (aa) protein. The deduced translated sequence has consensus GTP-binding sites and similarity to the human MxA sequence (RKFLKERLARL) that has been shown to be essential for resistance against vesicular stomatitis virus (VSV). The presence of Mx mRNA was investigated by Northern blot analysis in the endometrium of non-pregnant sheep and between days 8 and 127 of pregnancy. Mx expression was detected at high levels between day 13 and day 20 of pregnancy. Furthermore, eightfold higher levels of Mx mRNA were detected in the pregnant versus the non-pregnant uterine horn in unilaterally pregnant sheep. Mx mRNA can be induced in sheep endometrium by ovine trophoblast interferon (IFN-tau).
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PMID:An interferon-induced Mx protein: cDNA sequence and high-level expression in the endometrium of pregnant sheep. 750 76

Cellular mechanisms that control susceptibility to opportunistic infection in human immunodeficiency virus (HIV)-infected individuals remain poorly understood. HIV may induce certain cellular genes that restrict HIV replication and protect cells against other superinfecting viral pathogens. Indeed, HIV-infected monocytes resist infection by vesicular stomatitis virus (VSV). HIV-induced VSV interference in monocytes increases with time after HIV infection. Such interference was evident 6 h after HIV infection and reached maximal levels at 14 days. Monocytotropic but not T cell-tropic HIV strains elicited these effects, signaling a requirement for viral entry and/or replication. Viral interference was independent of interferon (IFN) and was unaffected by addition of neutralizing IFN-alpha and -beta antibodies. The well-described IFN-alpha-inducible antiviral pathways were examined to determine their relationship to the cellular mechanism(s) underlying VSV interference. HIV and IFN-alpha both induced the expression of 2-5A synthetase and Mx gene. In contrast, the guanylate-binding protein (GBP), 6-16, and 9-27 cellular genes were up-regulated by IFN-alpha but not HIV. MxA was detected in HIV-infected monocytes but not in uninfected monocytes. The association between Mx expression and resistance to VSV, coupled with previously described anti-VSV activities by human MxA, suggested that Mx may be an effector molecule for the HIV-induced anti-VSV activities. These results, taken together, suggest that HIV can induce antiviral cellular gene expression, independent of IFN.
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PMID:Regulation of interferon-alpha-inducible cellular genes in human immunodeficiency virus-infected monocytes. 750 41

MxA is an IFN-induced human protein which is located in the cytoplasm of induced cells. MxA makes the cells resistant to infection by influenza and vesicular stomatitis viruses. In the present work we used baculovirus expression system to produce MxA protein. The protein was purified to homogeneity and highly specific polyclonal anti-MxA antibodies were prepared. In human mononuclear cells, and A549 lung carcinoma cells expression of MxA protein is induced by very low (< 1 IU/ml) doses of leukocyte IFN-alpha (nIFN-alpha), whereas IFN-gamma does not seem to induce it or potentiate the induction by IFN-alpha. In mononuclear cells stimulated with high doses of leukocyte IFN-alpha concentrations, the amount of MxA mRNA was induced 10-fold at 4 h after IFN induction and up to 10-fold higher MxA protein levels were observed at 24-48 h postinduction. The gene can be reinduced by IFN-alpha 24 h after the initial induction suggesting for a lack of negative feedback after this time point. The protein is very stable, the half-life being approximately 2.3 days. Flow cytometric analysis revealed that monocytes have higher basal and induced MxA protein levels than lymphocytes but the dose-dependency of MxA expression is very similar in both cell types. Granulocytes are producing very low amounts of MxA protein.
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PMID:Control of IFN-inducible MxA gene expression in human cells. 767 92


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