Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism. Cancer patients with decreased DPD activity are at increased risk for severe toxicity including diarrhea, stomatitis, mucositis, myelosuppression, neurotoxicity, and, in some cases, death. We now report the first known cancer patient who developed life-threatening complications after treatment with topical 5-FU and was shown subsequently to have profound DPD deficiency. RT-PCR and genomic PCR methodologies were used to identify a G to A mutation in the GT 5' splicing recognition sequence of intron 14, resulting in a 165-bp deletion (corresponding to exon 14) in this patient's DPD mRNA. Immunoprecipitation and Western blot analysis were then used to demonstrate that the aberrant DPD mRNA is translated into a nonfunctional DPD protein that is ubiquitinated. We conclude that the presence of this metabolic defect combined with topical 5-FU (a drug demonstrating a narrow therapeutic index) results in the unusual presentation of life-threatening toxicity after treatment with a topical drug. These data further suggest that degradation by the ubiquitin-proteosome-mediated system plays a role in the elimination of the DPD protein.
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PMID:Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. 1047 70

The matrix (M) proteins of vesicular stomatitis virus (VSV) and rabies virus (RV) play a key role in both assembly and budding of progeny virions. A PPPY motif (PY motif or late-budding domain) is conserved in the M proteins of VSV and RV. These PY motifs are important for virus budding and for mediating interactions with specific cellular proteins containing WW domains. The PY motif and flanking sequences of the M protein of VSV were used as bait to screen a mouse embryo cDNA library for cellular interactors. The mouse Nedd4 protein, a membrane-localized ubiquitin ligase containing multiple WW domains, was identified from this screen. Ubiquitin ligase Rsp5, the yeast homolog of Nedd4, was able to interact both physically and functionally with full-length VSV M protein in a PY-dependent manner. Indeed, the VSV M protein was multiubiquitinated by Rsp5 in an in vitro ubiquitination assay. To demonstrate further that ubiquitin may be involved in the budding process of rhabdoviruses, proteasome inhibitors (e.g., MG132) were used to decrease the level of free ubiquitin in VSV- and RV-infected cells. Viral titers measured from MG132-treated cells were reproducibly 10- to 20-fold lower than those measured from untreated control cells, suggesting that free ubiquitin is important for efficient virus budding. Last, release of a VSV PY mutant was not inhibited in the presence of MG132, signifying that the functional L domain of VSV is required for the inhibitory effect exhibited by MG132. These data suggest that the cellular ubiquitin-proteasome machinery is involved in the budding process of VSV and RV.
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PMID:Rhabdoviruses and the cellular ubiquitin-proteasome system: a budding interaction. 1160 4

Influenza virus enters cells by endocytosis, and requires the low pH of the late endosome for successful infection. Here, we investigated the requirements for sorting into the multivesicular body pathway of endocytosis. We show that treatment of host cells with the proteasome inhibitors MG132 and lactacystin directly affects the early stages of virus replication. Unlike other viruses, such as retroviruses, influenza virus budding was not affected. The requirement for proteasome function was not shared by two other pH-dependent viruses: Semliki Forest virus and vesicular stomatitis virus. With MG132 treatment, incoming influenza viruses were retained in endosomes that partially colocalized with mannose 6-phosphate receptor, but not with classical markers of early or late endosomes. Colocalization was also observed with Rme-1, which is part of the recycling pathway of endocytosis. In addition, influenza virus entry was dependent on the vacuolar protein sorting pathway, as over-expression of dominant-negative hVPS4 caused arrest of viruses in endosome-like populations that partially colocalized with the hVPS4 protein. Overall, we conclude that influenza virus selectively requires the ubiquitin/vacuolar protein sorting pathway for entry into host cells, and that it must communicate with a specific cellular machinery for intracellular sorting during the initial phase of virus infection.
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PMID:The ubiquitin-vacuolar protein sorting system is selectively required during entry of influenza virus into host cells. 1461 49

ISG15 is an interferon-induced ubiquitin-like modifier which can be conjugated to distinct, but largely unknown, proteins. ISG15 has been implicated in a variety of biological activities, which encompass antiviral defense, immune responses, and pregnancy. Mice lacking UBP43 (USP18), the ISG15-deconjugating enzyme, develop a severe phenotype with brain injuries and lethal hypersensitivity to poly(I:C). It has been reported that an augmented conjugation of ISG15 in the absence of UBP43 induces prolonged STAT1 phosphorylation and that the ISG15 conjugation plays an important role in the regulation of JAK/STAT and interferon signaling (O. A. Malakhova, M. Yan, M. P. Malakhov, Y. Yuan, K. J. Ritchie, K. I. Kim, L. F. Peterson, K. Shuai, and D. E. Zhang, Genes Dev. 17:455-460, 2003). Here, we report that ISG15(-/-) mice are viable and fertile and display no obvious abnormalities. Lack of ISG15 did not affect the development and composition of the main cellular compartments of the immune system. The interferon-induced antiviral state and immune responses directed against vesicular stomatitis virus and lymphocytic choriomeningitis virus were not significantly altered in the absence of ISG15. Furthermore, interferon- or endotoxin-induced STAT1 tyrosine-phosphorylation, as well as expression of typical STAT1 target genes, remained unaffected by the lack of ISG15. Thus, ISG15 is dispensable for STAT1 and interferon signaling.
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PMID:ISG15, an interferon-stimulated ubiquitin-like protein, is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus. 1602 73

Effects of proteasome inhibitors on the replication of a paramyxovirus in comparison with the effects on replication of an orthomyxovirus and rhabdovirus were investigated. Treatment of Sendai virus (SeV)-infected LLC-MK2 cells with 50 microM MG132 reduced virus growth to ca. 1/10,000, and treatment with different concentrations of MG132 reduced virus growth in a dose-dependent manner. Released amounts of viral proteins were reduced in correspondence with decrease in infectivity. The inhibition of virus maturation was confirmed by an SeV-like particle formation system. Lactacystin also impaired SeV growth and zLL impaired the growth to a lesser extent, suggesting involvement of proteasomes in the restriction of virus growth. In the presence of MG132, localizations of the M protein and viral F and HN glycoproteins on the cell membrane appeared to be partly dissociated, although the viral glycoproteins were normally transported to the cell surface. These results suggest that an early step of SeV assembly was disturbed by proteasome inhibitors. The relationship of the results with ubiquitin is also discussed. SeV maturation was less susceptible and resistant to MG132 in CV1 cells and A549 cells, respectively, indicating cell specificity of the drug effect. Release of vesicular stomatitis virus also showed high susceptibility to MG132 and release of influenza virus A/WSN/33 was only mildly susceptible to the drug in LLC-MK2 cells. Effects of proteasome inhibitors on virus maturation are thus highly cell-specific and partly virus-specific.
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PMID:Cell-specific inhibition of paramyxovirus maturation by proteasome inhibitors. 1617 38

Activation of the interferon regulatory factors (IRFs) 3 and 7 transcription factors is essential for the induction of type I interferon (IFN) and development of the innate antiviral response. Retinoic acid-inducible gene I has been shown to contribute to virus-induced IFN production independent of the Toll-like receptor pathways in response to a variety of RNA viruses and double-stranded RNA. In the present study, we demonstrate that the NF-kappaB-inducible, anti-apoptotic protein A20 efficiently blocks RIG-I-mediated activation of NF-kappaB-, IRF-3-, and IRF-7-dependent promoters but only weakly interferes with TRIF-TLR-3-mediated IFN activation. Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding. The level of A20 inhibition was upstream of the TBK1/IKKepsilon kinases that phosphorylate IRF3 and IRF7 and paradoxically, A20 selectively degraded the TRIF protein but not RIG-I. A20 possesses two ubiquitin-editing domains, an N-terminal deubiquitination domain and a C-terminal ubiquitin ligase domain consisting of seven zinc finger domains. Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression. Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20. These results suggest that the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state.
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PMID:Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. 1630 43

UBP43/USP18 was described as a specific protease that removes conjugated ubiquitin-like modifier ISG15 from target proteins. The severe phenotype of UBP43(-/-) mice characterized by premature death, brain cell injury, and deregulated STAT1 signaling was ascribed to an enhanced conjugation of ISG15. In contrast, no phenotypic changes were detected in ISG15(-/-) mice. To verify the role of ISG15 in the phenotype of UBP43(-/-) mice, we employed mice deficient for both ISG15 and UBP43. Here, we show that the phenotype of UBP43(-/-) mice was not rescued by the absence of ISG15, as evident from unchanged mortality, neurological symptoms, and occurrence of hydrocephalus. Also, the reported hypersensitivity of UBP43(-/-) mice to an interferon inducer, poly(I . C), was ISG15 independent. Furthermore, no evidence for a role of ISG15 in the modulation of STAT1 signaling or in the resistance against lymphocytic choriomeningitis virus and vesicular stomatitis virus was found. Presented results clearly demonstrate that the phenotypic alterations of UBP43(-/-) mice are not caused by the lack of ISG15 deconjugation and must be due to another, non-ISG15-mediated molecular mechanism.
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PMID:Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice. 1631 24

The expression of ubiquitin-like modifier ISG15 and its conjugation to target proteins are highly induced by interferon (IFN) stimulation and during viral and bacterial infections. However, the biological significance of this modification has not been clearly understood. To investigate the function of protein modification by ISG15, we generated a mouse model deficient in UBE1L, an ISG15-activating enzyme. Ube1L-/- mice did not produce ISG15 conjugates but expressed free ISG15 normally. ISGylation has been implicated in the reproduction and innate immunity. However, Ube1L-/- mice were fertile and exhibited normal antiviral responses against vesicular stomatitis virus and lymphocytic choriomeningitis virus infection. Our results indicate that UBE1L and protein ISGylation are not critical for IFN-alpha/beta signaling via JAK/STAT activation. Moreover, using Ube1L/Ubp43 double-deficient mice, we showed that lack of UBP43, but not the increase of protein ISGylation, is related to the increased IFN signaling in Ubp43-deficient mice.
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PMID:Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling. 1638 39

Hypoxia-inducible factor (HIF) is a central regulator of cellular responses to hypoxia, and under normal oxygen tension the catalytic alpha subunit of HIF is targeted for ubiquitin-mediated destruction via the VHL-containing E3 ubiquitin ligase complex. Principally known for its association with oncogenesis, HIF has been documented to have a role in the antibacterial response. Interferons, cytokines with antiviral functions, have been shown to upregulate the expression of HIF-1alpha, but the significance of HIF in the antiviral response has not been established. Here, using renal carcinoma cells devoid of VHL or reconstituted with functional wild-type VHL or VHL mutants with various abilities to negatively regulate HIF as an ideal model system of HIF activity, we show that elevated HIF activity confers dramatically enhanced resistance to vesicular stomatitis virus (VSV)-mediated cytotoxicity. Inhibition of HIF activity using a small-molecule inhibitor, chetomin, enhanced cellular sensitivity to VSV, while treatment with hypoxia mimetic CoCl2 promoted resistance. Similarly, targeting HIF-2alpha by RNA interference also enhanced susceptibility to VSV. Expression profiling studies show that upon VSV infection, the induction of genes with known antiviral activity, such as that encoding beta interferon (IFN-beta), is significantly enhanced by HIF. These results reveal a previously unrecognized role of HIF in the antiviral response by promoting the expression of the IFN-beta gene and other genes with antiviral activity upon viral infection.
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PMID:Loss of VHL confers hypoxia-inducible factor (HIF)-dependent resistance to vesicular stomatitis virus: role of HIF in antiviral response. 1692 39

Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule in vivo. Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15-/- mice are more susceptible to influenza A/WSN/33 and influenza B/Lee/40 virus infections. ISG15-/- mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15-/- mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens.
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PMID:IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. 1722 66


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