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Endogenous AJAP1 associates with the cytoskeleton and attenuates angiogenesis in endothelial cells
(2017)
The adherens junction associated protein 1 (AJAP1, aka shrew-1) is presumably a type-I transmembrane protein localizing and interacting with the E-cadherin-catenin complex. In various tumors, AJAP1 expression is reduced or lost, including hepatocellular and esophageal squamous cell carcinoma, and glial-derived tumors. The aberrant expression of AJAP1 is associated with alterations in cell migration, invasion, increased tumor growth, and tumor vascularization, suggesting AJAP1 as a putative tumor suppressor. We show that AJAP1 attenuates sprouting angiogenesis by reducing endothelial migration and invasion capacities. Further, we show for the first time that endogenous AJAP1 is associated with the microtubule cytoskeleton. This linkage is independent from cell confluency and stable during angiogenic sprouting in vitro. Our work suggests that AJAP1 is a putative negative regulator of angiogenesis, reducing cell migration and invasion by interfering with the microtubule network. Based on our results and those of other authors, we suggest AJAP1 as a novel tumor suppressor and diagnostic marker.
The degradation of nonfunctional mitochondrial proteins is of fundamental relevance for maintenance of cellular homeostasis. The heteromeric CLPXP protein complex in the mitochondrial matrix is part of this process. In the fungal aging model Podospora anserina, ablation of CLPXP leads to an increase in healthy lifespan. Here, we report that this counterintuitive increase depends on a functional autophagy machinery. In PaClpXP mutants, autophagy is involved in energy conservation and the compensation of impairments in respiration. Strikingly, despite the impact on mitochondrial function, it is not mitophagy but general autophagy that is constitutively induced and required for longevity. In contrast, in another long-lived mutant ablated for the mitochondrial PaIAP protease, autophagy is neither induced nor required for lifespan extension. Our data provide novel mechanistic insights into the capacity of different forms of autophagy to compensate impairments of specific components of the complex mitochondrial quality control network and about the biological role of mitochondrial CLPXP in the control of cellular energy metabolism.
Motivation: Arabidopsis thaliana is a well-established model system for the analysis of the basic physiological and metabolic pathways of plants. Nevertheless, the system is not yet fully understood, although many mechanisms are described, and information for many processes exists. However, the combination and interpretation of the large amount of biological data remain a big challenge, not only because data sets for metabolic paths are still incomplete. Moreover, they are often inconsistent, because they are coming from different experiments of various scales, regarding, for example, accuracy and/or significance. Here, theoretical modeling is powerful to formulate hypotheses for pathways and the dynamics of the metabolism, even if the biological data are incomplete. To develop reliable mathematical models they have to be proven for consistency. This is still a challenging task because many verification techniques fail already for middle-sized models. Consequently, new methods, like decomposition methods or reduction approaches, are developed to circumvent this problem.
Methods: We present a new semi-quantitative mathematical model of the metabolism of Arabidopsis thaliana. We used the Petri net formalism to express the complex reaction system in a mathematically unique manner. To verify the model for correctness and consistency we applied concepts of network decomposition and network reduction such as transition invariants, common transition pairs, and invariant transition pairs.
Results: We formulated the core metabolism of Arabidopsis thaliana based on recent knowledge from literature, including the Calvin cycle, glycolysis and citric acid cycle, glyoxylate cycle, urea cycle, sucrose synthesis, and the starch metabolism. By applying network decomposition and reduction techniques at steady-state conditions, we suggest a straightforward mathematical modeling process. We demonstrate that potential steady-state pathways exist, which provide the fixed carbon to nearly all parts of the network, especially to the citric acid cycle. There is a close cooperation of important metabolic pathways, e.g., the de novo synthesis of uridine-5-monophosphate, the γ-aminobutyric acid shunt, and the urea cycle. The presented approach extends the established methods for a feasible interpretation of biological network models, in particular of large and complex models.
It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5’-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5’-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5’-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described.
Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs therefore requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies.
Background: As members of the Notothenioidei - the dominant fish taxon in Antarctic waters - the family Bathydraconidae includes 12 genera and 17 species. The knowledge of these species inhabiting an isolated environment is rather fragmentary, including their parasite fauna. Studies on fish hosts and their associated parasites can help gain insights into even remote ecosystems and be used to infer ecological roles in food webs; however, ecological studies on the Bathydraconidae are scarce.
Results: In this study, stomach contents and parasite fauna of the Antarctic dragonfish species Parachaenichthys charcoti (n = 47 specimens) as well as of Gerlachea australis (n = 5), Gymnodraco acuticeps (n = 9) and Racovitzia glacialis (n = 6) were examined. The parasite fauna of P. charcoti consisted of eight genera represented by 11 species, with three of them being new host records. Overall, 24 parasite genera and 26 species were found in the sampled fish, including eleven new host records.
Conclusion: Analyses revealed that the majority of the parasite species found in the different fish hosts are endemic to Antarctic waters and are characterized by a broad host range. These findings are evidence for the current lack of knowledge and the need for further parasitological studies of fish species in this unique habitat.
Reticulate evolution is considered to be among the main mechanisms of plant evolution, often leading to the establishment of new species. However, complex evolutionary scenarios result in a challenging definition of evolutionary and taxonomic units. In this study, we aimed to examine the evolutionary origin and revise the species status of Campanula baumgartenii, a rare endemic species from the polyploid complex Campanula section Heterophylla. Morphometry, flow cytometric ploidy estimation, amplified fragment length polymorphisms (AFLPs), as well as chloroplast and nuclear DNA sequence markers were used to assess the morphological and genetic differentiation among C. baumgartenii, Campanula rotundifolia and other closely related taxa. Tetra- and hexaploid C. baumgartenii is morphologically and molecularly (AFLP) differentiated from sympatric C. rotundifolia. Contrasting signals from nuclear (ITS) and chloroplast (trnL-rpl32) markers suggest a hybrid origin of C. baumgartenii with C. rotundifolia and a taxon related to the alpine Campanula scheuchzeri as ancestors. Additionally, hexaploid C. baumgartenii currently hybridizes with co-occurring tetraploid C. rotundifolia resulting in pentaploid hybrids, for which C. baumgartenii serves as both seed and pollen donor. Based on the molecular and morphological differentiation, we propose to keep C. baumgartenii as a separate species. This study exemplifies that detailed population genetic studies can provide a solid basis for taxonomic delimitation within Campanula section Heterophylla as well as for sound identification of conservation targets.
The iconic Australasian kangaroos and wallabies represent a successful marsupial radiation. However, the evolutionary relationship within the two genera, Macropus and Wallabia, is controversial: mitochondrial and nuclear genes, and morphological data have produced conflicting scenarios regarding the phylogenetic relationships, which in turn impact the classification and taxonomy. We sequenced and analyzed the genomes of 11 kangaroos to investigate the evolutionary cause of the observed phylogenetic conflict. A multilocus coalescent analysis using ∼14,900 genome fragments, each 10 kb long, significantly resolved the species relationships between and among the sister-genera Macropus and Wallabia. The phylogenomic approach reconstructed the swamp wallaby (Wallabia) as nested inside Macropus, making this genus paraphyletic. However, the phylogenomic analyses indicate multiple conflicting phylogenetic signals in the swamp wallaby genome. This is interpreted as at least one introgression event between the ancestor of the genus Wallabia and a now extinct ghost lineage outside the genus Macropus. Additional phylogenetic signals must therefore be caused by incomplete lineage sorting and/or introgression, but available statistical methods cannot convincingly disentangle the two processes. In addition, the relationships inside the Macropus subgenus M. (Notamacropus) represent a hard polytomy. Thus, the relationships between tammar, red-necked, agile, and parma wallabies remain unresolvable even with whole-genome data. Even if most methods resolve bifurcating trees from genomic data, hard polytomies, incomplete lineage sorting, and introgression complicate the interpretation of the phylogeny and thus taxonomy.
Mutations are the ultimate basis of evolution, yet their occurrence rate is known only for few species. We directly estimated the spontaneous mutation rate and the mutational spectrum in the nonbiting midge C. riparius with a new approach. Individuals from ten mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing parental genotypes. We identified 51 new single site mutations of which 25 were insertions or deletions and 26 single nucleotide mutations. This shift in the mutational spectrum compared to other organisms was explained by the high A/T content of the species. We estimated a haploid mutation rate of 2.1 × 10−9 (95% confidence interval: 1.4 × 10−9 – 3.1 × 10-9) that is in the range of recent estimates for other insects and supports the drift barrier hypothesis. We show that accurate mutation rate estimation from a high number of observed mutations is feasible with moderate effort even for nonmodel species.