Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates

BACKGROUND: The syndecans are the major family of transmembrane proteoglycans in animals and are known for multiple roles in cell interactions and growth factor signalling during development, inflammatory response, wound-repair and tumorigenesis. Although syndecans have been cloned from several invertebrate and vertebrate species, the extent of conservation of the family across the animal kingdom is unknown and there are gaps in our knowledge of chordate syndecans. Here, we develop a new level of knowledge for the whole syndecan family, by combining molecular phylogeny of syndecan protein sequences with analysis of the genomic contexts of syndecan genes in multiple vertebrate organisms. RESULTS: We identified syndecan-encoding sequences in representative Cnidaria and throughout the Bilateria. The C1 and C2 regions of the cytoplasmic domain are highly conserved throughout the animal kingdom. We identified in the variable region a universally-conserved leucine residue and a tyrosine residue that is conserved throughout the Bilateria. Of all the genomes examined, only tetrapod and fish genomes encode multiple syndecans. No syndecan-1 was identified in fish. The genomic context of each vertebrate syndecan gene is syntenic between human, mouse and chicken, and this conservation clearly extends to syndecan-2 and -3 in T. nigroviridis. In addition, tetrapod syndecans were found to be encoded from paralogous chromosomal regions that also contain the four members of the matrilin family. Whereas the matrilin-3 and syndecan-1 genes are adjacent in tetrapods, this chromosomal region appears to have undergone extensive lineage-specific rearrangements in fish. CONCLUSION: Throughout the animal kingdom, syndecan extracellular domains have undergone rapid change and elements of the cytoplasmic domains have been very conserved. The four syndecan genes of vertebrates are syntenic across tetrapods, and synteny of the syndecan-2 and -3 genes is apparent between tetrapods and fish. In vertebrates, each of the four family members are encoded from paralogous genomic regions in which members of the matrilin family are also syntenic between tetrapods and fish. This genomic organization appears to have been set up after the divergence of urochordates (Ciona) and vertebrates. The syndecan-1 gene appears to have been lost relatively early in the fish lineage. These conclusions provide the basis for a new model of syndecan evolution in vertebrates and a new perspective for analyzing the roles of syndecans in cells and whole organisms

Hydrogen sulfide and nitric oxide metabolites in the blood of free-ranging brown bears and their potential roles in hibernation

During winter hibernation, brown bears (Ursus arctos) lie in dens for half a year without eating while their basal metabolism is largely suppressed. To understand the underlying mechanisms of metabolic depression in hibernation, we measured type and content of blood metabolites of two ubiquitous inhibitors of mitochondrial respiration, hydrogen sulfide (H2S) and nitric oxide (NO), in winter-hibernating and summer-active free-ranging Scandinavian brown bears. We found that levels of sulfide metabolites were overall similar in summer-active and hibernating bears but their composition in the plasma differed significantly, with a decrease in bound sulfane sulfur in hibernation. High levels of unbound free sulfide correlated with high levels of cysteine (Cys) and with low levels of bound sulfane sulfur, indicating that during hibernation H2S, in addition to being formed enzymatically from the substrate Cys, may also be regenerated from its oxidation products, including thiosulfate and polysulfides. In the absence of any dietary intake, this shift in the mode of H2S synthesis would help preserve free Cys for synthesis of glutathione (GSH), a major antioxidant found at high levels in the red blood cells of hibernating bears. In contrast, circulating nitrite and erythrocytic S-nitrosation of glyceraldehyde-3-phosphate dehydrogenase, taken as markers of NO metabolism, did not change appreciably. Our findings reveal that remodeling of H2S metabolism and enhanced intracellular GSH levels are hallmarks of the aerobic metabolic suppression of hibernating bear

Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

Cell protrusions contribute to cell motility and migration by mediating the outward extension and initial adhesion of cell edges. In many cells, these extensions are supported by actin bundles assembled by the actin cross-linking protein, fascin. Multiple extracellular cues regulate fascin and here we focus on the mechanism by which the transmembrane proteoglycan, syndecan-1, specifically activates lamellipodial cell spreading and fascin-and-actin bundling when clustered either by thrombospondin-1, laminin, or antibody to the syndecan-1 extracellular domain. There is almost no knowledge of the signaling mechanisms of syndecan-1 cytoplasmic domain and we have tested the hypothesis that the unique V region of syndecan-1 cytoplasmic domain has a crucial role in these processes. By four criteria—the activities of N-cadherin/V region chimeras, syndecan-1 deletion mutants, or syndecan-1 point mutants, and specific inhibition by a membrane-permeable TAT-V peptide—we demonstrate that the V region is necessary and sufficient for these cell behaviors and map the molecular basis for its activity to multiple residues located across the V region. These activities correlate with a V-region-dependent incorporation of cell-surface syndecan-1 into a detergent-insoluble form. We also demonstrate functional roles of syndecan-1 V region in laminin-dependent C2C12 cell adhesion and three-dimensional cell migration. These data identify for the first time specific cell behaviors that depend on signaling through the V region of syndecan-1

Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates-6

<p><b>Copyright information:</b></p><p>Taken from "Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates"</p><p>BMC Genomics 2006;7():83-83.</p><p>Published online 18 Apr 2006</p><p>PMCID:PMC1464127.</p><p>Copyright © 2006 Chakravarti and Adams; licensee BioMed Central Ltd.</p> in an ancestral chordate (chordate 2) subsequent to the divergence of the Urochordate lineage. The model assumes that four-fold paralogy was then set up in an ancestral vertebrate as a result of two rounds of whole-genome duplication. This process also sets up pairing within each set of paralogues. The lower right hand panel represents how the initial complete paralogy has degenerated through gene rearrangements in modern tetrapods. Fish underwent an additional round of genome duplication that would have generated additional paralogous pairs [58]. The lower left-hand panel represents the situation in two modern fish, in which only the two matrilin-3 paralogues have been retained from FSGD. The syndecan-1 locus appears to have been lost early in the fish lineage. Other gene rearrangements or losses appear specific to the zebrafish or pufferfish lineages

Autophagic checks and balances of cellular immune responses

IRF3 (interferon regulatory factor 3) is a critical component of the antiviral innate immune response. IRF3 deficiency causes detrimental effects to the host during virus infection. Dysregulation of IRF3 functions is associated with viral, inflammatory, and hepatic diseases. Both transcriptional and pro-apoptotic activities of IRF3 are involved in the exacerbated inflammation and apoptosis in liver injury induced by ethanol and high-fat diets. Therefore, regulation of IRF3 activities has consequences, and it is a potential therapeutic target for infectious and inflammatory diseases. We recently revealed that IRF3 is degraded by a small molecule, auranofin, by activating the cellular macroautophagy/autophagy pathway. Autophagy is a catabolic pathway that contributes to cellular homeostasis and antiviral host defense. Degradation of IRF3 by autophagy may be a novel strategy used by the viruses to their benefit. In addition, IRF3 functions are harmful in other diseases, including liver injury and bacterial infection. A better understanding of the role of autophagy in regulating IRF3 functions has significant implications in developing therapeutic strategies. Therefore, autophagy provides checks and balances in the innate immune response

Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates-5

<p><b>Copyright information:</b></p><p>Taken from "Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates"</p><p>BMC Genomics 2006;7():83-83.</p><p>Published online 18 Apr 2006</p><p>PMCID:PMC1464127.</p><p>Copyright © 2006 Chakravarti and Adams; licensee BioMed Central Ltd.</p>ing genes with human, mouse and chicken, as shown in Fig. 3, and with each other. Partial synteny was identified. Each diagram represents the order of genes along a portion of the indicated chromosomes. Each horizontal line represents a gene: red lines represent genes that are syntenic and black lines represent non-conserved intervening genes. The numbers indicate the exact location in nucleotides of each region on its respective chromosome in each species. HUGO gene names are given, and the matrilin genes are indicated in red

Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates-4

<p><b>Copyright information:</b></p><p>Taken from "Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates"</p><p>BMC Genomics 2006;7():83-83.</p><p>Published online 18 Apr 2006</p><p>PMCID:PMC1464127.</p><p>Copyright © 2006 Chakravarti and Adams; licensee BioMed Central Ltd.</p>he "dataset of paralogons in the human genome v5.28" 57. Each block number and the exact location of the paralogous regions on the respective chromosomes are also shown. Shaded lines represent how the original blocks were modified to include missing syndecan genes (see methods)

Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates-1

<p><b>Copyright information:</b></p><p>Taken from "Comparative genomics of the syndecans defines an ancestral genomic context associated with matrilins in vertebrates"</p><p>BMC Genomics 2006;7():83-83.</p><p>Published online 18 Apr 2006</p><p>PMCID:PMC1464127.</p><p>Copyright © 2006 Chakravarti and Adams; licensee BioMed Central Ltd.</p>e matrix output was used to prepared an unrooted phylogenetic diagram in DRAWTREE. Key is the same as in Figure 1. Scale bar = 0.1 substitution/site