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Clinical and Experimental Pharmacology... Jul 2022Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to...
Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET-1-mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho-Smad2L) regulate GAG synthesising enzymes mRNA expression (C4ST-1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesising enzymes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). ET-1 treatment of human VSMCs resulted in an increase in phospho-Smad2L level. The TGF-β receptor antagonist, SB431542 and the mixed ET and ET receptor antagonist bosentan, inhibited ET-1-mediated phospho-Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET-1-mediated phospho-Smad2L levels were inhibited. The gene expression levels of GAG synthesising enzymes post-ET-1 treatment were increased compared to untreated controls (p < 0.01). The ET-mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N-acetyl-L-cysteine (NAC). ET-1-mediated signalling to GAG synthesising enzymes gene expression occurs via transactivation-dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation.
Topics: Bosentan; Endothelin-1; Genes, gag; Glycosaminoglycans; Humans; NADPH Oxidases; Phosphorylation; RNA, Messenger
PubMed: 35527471
DOI: 10.1111/1440-1681.13650 -
Life (Basel, Switzerland) Mar 2022The most important sources of new components of genomes are transposable elements, which can occupy more than half of the nucleotide sequence of the genome in higher... (Review)
Review
The most important sources of new components of genomes are transposable elements, which can occupy more than half of the nucleotide sequence of the genome in higher eukaryotes. Among the mobile components of a genome, a special place is occupied by retroelements, which are similar to retroviruses in terms of their mechanisms of integration into a host genome. The process of positive selection of certain sequences of transposable elements and retroviruses in a host genome is commonly called molecular domestication. There are many examples of evolutionary adaptations of (retroviral capsid) sequences as new regulatory sequences of different genes in mammals, where domesticated genes take part in placenta functioning and embryogenesis, regulation of apoptosis, hematopoiesis, and metabolism. The only -related gene has been found in the genome-. According to the large-scale transcriptomic and proteomic analysis data, the gene in is a component of the protein complex involved in the stress response. In this work, we consider the evolutionary processes that led to the formation of a new function of the domesticated gene and its adaptation to participation in the stress response. We discuss the possible functional role of the Gagr as part of the complex with its partners in , and the pathway of evolution of proteins of the complex in eukaryotes to determine the benefit of the domesticated retroelement gene.
PubMed: 35330115
DOI: 10.3390/life12030364 -
Immunology Letters Jul 2020Endogenous retrovirus (ERV) are remnants of ancient retroviruses that have been incorporated into the genome and evidence suggests that they may play a role in the...
Endogenous retrovirus (ERV) are remnants of ancient retroviruses that have been incorporated into the genome and evidence suggests that they may play a role in the etiology of T1D. We previously identified a murine leukemia retrovirus-like ERV whose Env and Gag antigens are involved in autoimmune responses in non-obese diabetic (NOD) mice. In this study, we show that the Gag antigen is present in the islet stromal cells. Although Gag gene transcripts were present, Gag protein was not detected in diabetes-resistant mice. Cloning and sequencing analysis of individual Gag genes revealed that NOD islets express Gag gene variants with complete open-reading frames (ORFs), in contrast to the diabetes-resistant mice, whose islet Gag gene transcripts are mostly non-ORFs. Importantly, the ORFs obtained from the NOD islets are extremely heterogenous, coding for various mutants that are absence in the genome. We further show that Gag antigens are stimulatory for autoreactive T cells and identified one islet-expressing Gag variant that contains an altered peptide ligand capable of inducing IFN-gamma release by the T cells. The data highlight a unique retrovirus-like factor in the islets of the NOD mouse strain, which may participate in key events triggering autoimmunity and T1D.
Topics: Animals; Autoantigens; Cell-Derived Microparticles; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endogenous Retroviruses; Gene Products, gag; Humans; Interferon-gamma; Islets of Langerhans; Lymphocyte Activation; Mice; Mice, Inbred NOD; T-Lymphocytes
PubMed: 32335144
DOI: 10.1016/j.imlet.2020.04.007 -
Molecular Biology and Evolution Dec 2021Vertebrate genomes contain endogenous retroviruses (ERVs) that represent remnants of past germline infections by ancient retroviruses. Despite comprising 8% of the human...
Vertebrate genomes contain endogenous retroviruses (ERVs) that represent remnants of past germline infections by ancient retroviruses. Despite comprising 8% of the human genome, the human ERVs (HERVs) do not encode a replication competent retrovirus. However, some HERV genes have been co-opted to serve host functions, most notably the viral envelope-derived syncytins involved in placentation. Here, we identify the oldest HERV intact gag gene with an open reading frame, gagV1. Its provirus contains an intact env, envV1, and the first open reading frame found in an HERV gag leader, pre-gagV1, which encodes a novel protein. This HERV is linked to a related gag gene, gagV3, and these three genes all show patterns of evolutionary conservation in primates. gagV1 and pre-gagV1 orthologs are present in all simian primate lineages indicating that this HERV entered the germline of the common simian primate ancestor at least 43 Ma, whereas gagV3 is found in Old and New World monkeys. gagV1 and gagV3 have undergone recurrent gene conversion events and positive selection. Expression of gagV1, gagV3, and pre-gagV1 is restricted to the placenta in humans and macaques suggesting co-option for placenta-specific host functions. Transcriptomic analysis of human tumors also found upregulated levels of gagV1 transcripts in diffuse large B-cell lymphomas. These findings suggest that these HERV-V genes may be useful markers for the most common type of non-Hodgkin's lymphoma and that they may have contributed to the successive domestications of env and gag genes in eutherians involved in the ongoing ERV-driven evolution of the placenta.
Topics: Animals; Endogenous Retroviruses; Female; Genes, gag; Humans; Lymphoma, Large B-Cell, Diffuse; Placenta; Pregnancy; Primates
PubMed: 34410386
DOI: 10.1093/molbev/msab245 -
Molecular Biology and Evolution Jul 2021LTR retrotransposons comprise a major component of the genomes of eukaryotes. On occasion, retrotransposon genes can be recruited by their hosts for diverse functions, a...
LTR retrotransposons comprise a major component of the genomes of eukaryotes. On occasion, retrotransposon genes can be recruited by their hosts for diverse functions, a process formally referred to as co-option. However, a comprehensive picture of LTR retrotransposon gag gene co-option in eukaryotes is still lacking, with several documented cases exclusively involving Ty3/Gypsy retrotransposons in animals. Here, we use a phylogenomic approach to systemically unearth co-option of retrotransposon gag genes above the family level of taxonomy in 2,011 eukaryotes, namely co-option occurring during the deep evolution of eukaryotes. We identify a total of 14 independent gag gene co-option events across more than 740 eukaryote families, eight of which have not been reported previously. Among these retrotransposon gag gene co-option events, nine, four, and one involve gag genes of Ty3/Gypsy, Ty1/Copia, and Bel-Pao retrotransposons, respectively. Seven, four, and three co-option events occurred in animals, plants, and fungi, respectively. Interestingly, two co-option events took place in the early evolution of angiosperms. Both selective pressure and gene expression analyses further support that these co-opted gag genes might perform diverse cellular functions in their hosts, and several co-opted gag genes might be subject to positive selection. Taken together, our results provide a comprehensive picture of LTR retrotransposon gag gene co-option events that occurred during the deep evolution of eukaryotes and suggest paucity of LTR retrotransposon gag gene co-option during the deep evolution of eukaryotes.
Topics: Animals; Biological Evolution; Eukaryota; Genes, gag; Retroelements; Selection, Genetic
PubMed: 33871607
DOI: 10.1093/molbev/msab101 -
Journal of Virology Jun 1984The nucleotide sequence of the gag gene of feline leukemia virus and its flanking sequences were determined and compared with the corresponding sequences of two strains... (Comparative Study)
Comparative Study
The nucleotide sequence of the gag gene of feline leukemia virus and its flanking sequences were determined and compared with the corresponding sequences of two strains of feline sarcoma virus and with that of the Moloney strain of murine leukemia virus. A high degree of nucleotide sequence homology between the feline leukemia virus and murine leukemia virus gag genes was observed, suggesting that retroviruses of domestic cats and laboratory mice have a common, proximal evolutionary progenitor. The predicted structure of the complete feline leukemia virus gag gene precursor suggests that the translation of nonglycosylated and glycosylated gag gene polypeptides is initiated at two different AUG codons. These initiator codons fall in the same reading frame and are separated by a 222-base-pair segment which encodes an amino terminal signal peptide. The nucleotide sequence predicts the order of amino acids in each of the individual gag-coded proteins (p15, p12, p30, p10), all of which derive from the gag gene precursor. Stable stem-and-loop secondary structures are proposed for two regions of viral RNA. The first falls within sequences at the 5' end of the viral genome, together with adjacent palindromic sequences which may play a role in dimer linkage of RNA subunits. The second includes coding sequences at the gag-pol junction and is proposed to be involved in translation of the pol gene product. Sequence analysis of the latter region shows that the gag and pol genes are translated in different reading frames. Classical consensus splice donor and acceptor sequences could not be localized to regions which would permit synthesis of the expected gag-pol precursor protein. Alternatively, we suggest that the pol gene product (RNA-dependent DNA polymerase) could be translated by a frameshift suppressing mechanism which could involve cleavage modification of stems and loops in a manner similar to that observed in tRNA processing.
Topics: Amino Acid Sequence; Animals; Antigens, Viral; Base Sequence; Cats; DNA Restriction Enzymes; Gene Products, gag; Genes; Genes, Viral; Leukemia Virus, Feline; Retroviridae; Species Specificity; Viral Proteins
PubMed: 6328019
DOI: 10.1128/JVI.50.3.884-894.1984 -
Blood Mar 2016Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected... (Review)
Review
Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.
Topics: Animals; B-Lymphocytes; Cell Transformation, Viral; Clone Cells; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, gag; Germinal Center; HIV; HIV Antigens; Humans; Immunocompromised Host; Lymphocyte Activation; Lymphoma, AIDS-Related; Lymphoma, B-Cell; Mice; Mice, Transgenic; Tumor Microenvironment; gag Gene Products, Human Immunodeficiency Virus
PubMed: 26773045
DOI: 10.1182/blood-2015-11-681411 -
Journal of Virology Jul 2019Endogenous retroviruses, records of past retroviral infections, are ubiquitous in vertebrate genomes. On occasion, vertebrate hosts have co-opted retroviral genes for...
Endogenous retroviruses, records of past retroviral infections, are ubiquitous in vertebrate genomes. On occasion, vertebrate hosts have co-opted retroviral genes for their own biological functions. Here, we perform a phylogenomic survey of retroviral gene homologs within vertebrate genomes and identify two ancient co-opted retroviral genes, designated () and (), in mammals. Conserved synteny and evolutionary analyses suggest that the and co-options occurred before the origin of modern placental mammals (∼100 million years ago) and before the origin of modern marsupials (∼80 million years ago), respectively. We found that the genes were lost or pseudogenized multiple times during the evolutionary course of mammals. While the gene is mainly subject to negative selection in placental mammals (except in Perissodactyla), the gene underwent positive selection in marsupials. Moreover, analyses of transcriptome-sequencing (RNA-seq) data suggest that the and the genes are expressed in a wide range of tissues. The convergent co-option in mammals implies the retroviral gene might have been repurposed more frequently than previously thought. Retroviruses occasionally can infect host germ lines, forming endogenous retroviruses. Vertebrates, in turn, recruited retroviral genes for their own biological functions, a process formally known as co-option or exaptation. To date, co-opted retroviral genes have rarely been reported. In this study, we identified two co-opted retroviral genes, designated () and (), in mammals. The co-option of and occurred before the origin of modern placentals and before the origin of modern marsupials, respectively. Our study indicates that retroviral gene co-option might have occurred more frequently than previously thought during the evolutionary course of vertebrates.
Topics: Animals; Endogenous Retroviruses; Evolution, Molecular; Gene Products, gag; Humans; Marsupialia
PubMed: 31068420
DOI: 10.1128/JVI.00542-19 -
Virology Feb 2014The domestication of foreign genes is a powerful mechanism for new gene formation and genome evolution. It is known that domesticated retroviral gag genes in mammals not...
The domestication of foreign genes is a powerful mechanism for new gene formation and genome evolution. It is known that domesticated retroviral gag genes in mammals not only take part in protecting against viral infection but also control cell division, apoptosis, function of the placenta, and other biological processes. In this study, we focused on the domesticated retroviral gag gene homolog (Grp) in the Drosophila melanogaster genome. According to the results of a bioinformatic analysis, the Grp gene product is primarily under purifying selection in Drosophilidae family. The Grp protein has been shown to be transmembrane. The Grp gene is expressed at the adult stage of D. melanogaster in gender-specific and tissue-specific manner. Also the Grp gene expression is increased in response to the gypsy retrovirus. A function of the protein as a component of the endosomic membrane is considered.
Topics: Amino Acid Sequence; Animals; Checkpoint Kinase 1; Drosophila Proteins; Drosophila melanogaster; Evolution, Molecular; Female; Genes, gag; Male; Molecular Sequence Data; Organ Specificity; Phylogeny; Protein Kinases; Retroviridae; Sequence Alignment
PubMed: 24503082
DOI: 10.1016/j.virol.2013.12.024 -
Journal of Virology Nov 1998TED (transposable element D) is an env-containing member of the gypsy family of retrotransposons that represents a possible retrovirus of invertebrates. This...
TED (transposable element D) is an env-containing member of the gypsy family of retrotransposons that represents a possible retrovirus of invertebrates. This lepidopteran (moth) retroelement contains gag and pol genes that encode proteins capable of forming viruslike particles (VLP) with reverse transcriptase. Since VLP are likely intermediates in TED transposition, we investigated the roles of gag and pol in TED capsid assembly and maturation. By using constructed baculovirus vectors and TED Gag-specific antiserum, we show that the principal translation product of gag (Pr55(gag)) is cleaved to produce a single VLP structural protein, p37(gag). Replacement of Asp436 within the retrovirus-like active site of the pol-encoded protease (PR) abolished Pr55(gag) cleavage and demonstrated the requirement for PR in capsid processing. As shown by expression of an in-frame fusion of TED gag and pol, PR is derived from the Gag-Pol polyprotein Pr195(gag-pol). The PR cleavage site within Pr55(gag) was mapped to a position near the junction of a basic, nucleocapsid-like domain and a C-terminal acidic domain. Once released by cleavage, the C-terminal fragment was not detected. This acidic fragment was dispensable for VLP assembly, as demonstrated by the formation of VLP by C-terminal Pr55(gag) truncation proteins and replacement of the acidic domain with a heterologous protein. In contrast, C-terminal deletions that extended into the adjacent nucleocapsid-like domain of Pr55(gag) abolished VLP recovery and demonstrated that this central region contributes to VLP assembly or stability, or both. Collectively, these data suggest that the single TED protein p37(gag) provides both capsid and nucleocapsid functions. TED may therefore use a simple processing strategy for VLP assembly and genome packaging.
Topics: Amino Acid Sequence; Animals; Base Sequence; Cell Line; DNA Primers; DNA, Viral; Endogenous Retroviruses; Fusion Proteins, gag-pol; Gene Products, gag; Gene Products, pol; Genes, gag; Genes, pol; Kinetics; Models, Biological; Moths; Mutation; Nucleopolyhedroviruses; Protein Processing, Post-Translational; Retroelements; Spodoptera
PubMed: 9765414
DOI: 10.1128/JVI.72.11.8718-8724.1998