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Institute
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- Biochemie und Chemie (7)
Downy mildews caused by obligate biotrophic oomycetes result in severe crop losses worldwide. Among these pathogens, Pseudoperonospora cubensis and P. humuli, two closely related oomycetes, adversely affect cucurbits and hop, respectively. Discordant hypotheses concerning their taxonomic relationships have been proposed based on host–pathogen interactions and specificity evidence and gene sequences of a few individuals, but population genetics evidence supporting these scenarios is missing. Furthermore, nuclear and mitochondrial regions of both pathogens have been analyzed using microsatellites and phylogenetically informative molecular markers, but extensive comparative population genetics research has not been done. Here, we genotyped 138 current and historical herbarium specimens of those two taxa using microsatellites (SSRs). Our goals were to assess genetic diversity and spatial distribution, to infer the evolutionary history of P. cubensis and P. humuli, and to visualize genome-scale organizational relationship between both pathogens. High genetic diversity, modest gene flow, and presence of population structure, particularly in P. cubensis, were observed. When tested for cross-amplification, 20 out of 27 P. cubensis-derived gSSRs cross-amplified DNA of P. humuli individuals, but few amplified DNA of downy mildew pathogens from related genera. Collectively, our analyses provided a definite argument for the hypothesis that both pathogens are distinct species, and suggested further speciation in the P. cubensis complex.
Fatty acids in oomycetes
(2021)
In the published article, there was an error regarding the affiliation for Diana Abondano Almeida. As well as having affiliation 2, they should also have Department of Wildlife-/Zoo-Animal-Biology and Systematics, Faculty of Biological Sciences, Goethe Universität, Frankfurt, Germany.
The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
Cellular communication is a concept that can be explained as the transfer of signals or material (such as cytokines, ions, small molecules) between cells from the same or different type, across either short or long distances. Once this signal or material is received, it will, as a rule, promote a functional effect. Several routes, involved in this transfer, are well described and are of global importance for organ/tissue communication in an organism.
The brain interacts dynamically with the immune system, and the main route known to mediate this communication, is via the release of cytokines (by peripheral blood cells), which can then activate certain brain cell types, such as microglia, directly, or activate the vagus nerve transferring signals to neuronal populations in the brain. The communication between these two systems plays a key role in the pathophysiology of neurodegenerative diseases, and the mechanisms involved in this interaction are of central importance for understanding disease initiation and progression and search for therapeutic models.
The Momma lab previously addressed the mechanisms of interaction between the peripheral immune system and the brain by investigating cellular fusion of haematopoietic cells with neurons after inflammation. They addressed the question of whether this phenomenon also occurs under non-invasive conditions. To approach this problem, a genetic tracing model that relies on the Cre-Lox recombination system was used. Transgenic mice expressing Cre recombinase specifically in the haematopoietic lineage were crossed into a Cre-reporter background, thus all haematopoietic cells irreversibly express the reporter marker-gene EYFP. Using this model, EYFP was detected in non-haematopoietic tissues, suggesting the existence of a communication mechanism never described before. As cells containing two nuclei were never detected, fusion as a mechanism was excluded, suggesting that Cre reaches non-haematopoietic cells via a different signalling pathway. The Momma lab investigated whether the transfer of material through extracellular vesicles (EVs) could be behind this periphery-to-brain communication. Using the genetic mouse model, they were able to trace the transfer of Cre RNA via EVs between cells in vivo, generating the first in vivo evidence of functional RNA transfer by EVs between blood and brain.
The last decade has witnessed a rapid expansion of the field of EVs. Initially considered as waste disposal material, recent evidence has challenged this view. EVs are currently considered as a widespread intercellular communication system that can transport and transfer all types of biomolecules, from nucleic acids to lipids and proteins. However, several important questions are still under investigation. One of them is whether EVs are involved in brain pathophysiology, as inflammation plays an important role in onset and progression of neurodegenerative diseases and is well described in Parkinson Disease (PD). Based on preliminary data in a mouse, peripherally injected with a low dose of Lipopolysaccharide (LPS, an endotoxin found in the outer-membrane of Gram-negative bacteria, which causes an immune response), neurons and other cell population in the brain take up EVs from the periphery. Particularly, dopaminergic neurons from Substantia Nigra and Ventral Tegmental Area have been shown to receive functional RNA, transported through EVs, which can lead up to 20% of recombination. Furthermore, different neuronal populations from Hippocampus, Cortex and Cerebellum exhibit recombination, indicating a widespread signalling from blood to the brain. Therefore, the goal of my PhD thesis was to investigate the mechanisms of this transfer and the triggers that lead to EV uptake by neural cells in vivo both in pathological and physiological conditions.
In this project, the extent and function of EV-mediated signalling from blood to brain is explored in the context of peripheral inflammation and neurodegenerative diseases. Firstly, EVs isolated from WT mice were further characterized using size-exclusion chromatography (SEC), Western Blot (WB) and electron microscopy in order to extend the knowledge from previous work done in the Momma lab. Secondly, to expand on the biological relevance of the fact that inflammation is correlated with an increase in EV uptake, different approaches using the genetic murine tracing model were used. Recombination events from haematopoietic cells to the brain have been followed after peripheral injection of LPS. Peripheral inflammation caused by LPS injection led to widespread recombination events in the brain, specifically in microglia and neurons, including dopaminergic (DA) neurons. In contrast, astrocytes, oligodendrocytes and endothelial cells were never or very rarely recombined. Additionally, peripheral LPS injection in a murine model, where Cre is expressed only in erythrocytes, led to recombination events only in microglia, suggesting that the type of EV-secreting cell plays a role in the targeting of EVs to a specific cell population.
Non-ribosomal peptide synthetase docking domains : structure, function and engineering strategies
(2021)
Non-ribosomal peptide synthetases (NRPSs) are known for their capability to produce a wide range of natural compounds and some of them possess interesting bioactivities relevant for clinical application like antibiotics, anticancer, and immunosuppressive drugs. The diverse bioactivity of non-ribosomal peptides (NRPs) originates from their structural diversity, which results not only from the incorporation of non-proteinogenic amino acids into the growing peptide chain, but also the formation of heterocycles or further peptide modifications like methylation, hydroxylation and acetylation.
The biosynthesis of NRPs is achieved via the orchestrated interplay of distinct catalytic domains, which are grouped to modules that are located on one or more polypeptide chains. Each cycle starts with the selection and activation of a specific amino acid by the adenylation (A) domain, which catalyzes the aminoacyl adenylate formation under ATP consumption. This activated amino acid is then bound via a thioester bond to the 4’-phosphopantetheine cofactor (PPant-arm) of the following thiolation (T) domain. Before substrate loading, the PPant-arm is post-translationally added to the T domain by a phosphopantetheinyl transferase (PPTase), which converts the inactive apo-T domain in its active holo-form. In the last step of the catalytic cycle, two T domain bound peptide building blocks are connected by the condensation (C) domain, resulting in peptide bond formation and transfer of the nascent peptide chain to the following module. Each catalytic cycle is performed by a C-A-T elongation module until the termination module with a C-terminal thioesterase (TE) domain is reached. Here, the peptide product is released by hydrolysis or intramolecular cyclisation.
In comparison to single-protein NRPSs, where all modules are encoded on a single polypeptide chain, multi-protein NRPS systems must also maintain a specific module order during the peptide biosynthesis. Therefore, small C-terminal and N-terminal communication-mediating (COM) domains/docking domains (DD) were identified in the C- and N-terminal regions of multi-protein NRPSs. It was shown that these domains mediate specific and selective non-covalent protein-protein interaction, even though DD interactions are generally characterized by low affinities.
The first publication of this work focuses on the Peptide-Antimicrobial-Xenorhabdus peptide-producing NRPS called PaxS, which consists of the three proteins PaxA, PaxB and PaxC. Here, in particular the trans DD interface between the C-terminal attached DD of PaxB and N-terminal attached DD of PaxC was structurally investigated and thermodynamically characterized by isothermal titration calorimetry (ITC), yielding a dissociation constant (KD) of ~25 µM, which is a DD typical affinity known from further characterized DD pairs. The artificial linking of the PaxB/C C/NDD pair via a glycine-serine (GS) linker facilitated the structure determination of the DD complex by solution nuclear magnetic resonance (NMR) spectroscopy. In comparison to known docking domain structures, this DD complex assembles in a completely new fold which is characterized by a central α-helix of PaxC NDD wrapped in two V-shaped α-helices of PaxB CDD.
The first manuscript of this work focuses on the application of synthetic zippers (SZ) to mimic natural docking domains, enabling the easy assembly of NRPS building blocks encoded on different plasmids in a functional way. Here, the high-affinity interaction of SZs unambiguously defines the order of the synthetases derived from single-protein NRPSs in the engineered NRPS system and allows the recombination in a plug-and-play manner. Notably, the SZ engineering strategy even facilitates the functional assembly of NRPSs derived from Gram-positive and Gram-negative bacteria. Furthermore, the functional incorporation of SZs into NRPS modules is not limited to a specific linker region, so we could introduce them within all native NRPS linker regions (A-T, T-C, C-A).
The second publication and the second manuscript of this thesis again focus on the multi-protein PaxS, in particular on the trans interface between the proteins PaxA and PaxB on a molecular level by solution NMR. Therefore, the PaxA CDD adjacent T domain was included into the structural investigation besides the native interaction partner PaxB NDD. Before a three-dimensional structure could be obtained from NMR data, the NH groups located in the peptide bonds had to be assigned to the respective amino acids of the proteins (backbone assignment). Based on these backbone assignments, the secondary structure of PaxA T1-CDD and PaxB NDD in the absence and presence of the respective interaction partner were predicted.
The structural and functional characterization of the PaxA T1-CDD:PaxB NDD complex is summarized in manuscript two. The thermodynamic analysis of this complex by ITC determined a KD value of ~250 nM, whereas the discrete DDs did not interact at all. The high-affinity interaction allowed to determine the solution NMR structure of the PaxA T1-CDD:PaxB NDD complex without the covalent linkage of the interaction partners and an extended docking domain interface could be determined. This interface comprises on the one hand α-helix 4 of the PaxA T1 domain together with the α-helical CDD, and on the other hand the PaxB NDD, which is composed of two α-helices separated by a sharp bend.
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Most cellular processes are regulated by RNA-binding proteins (RBPs). These RBPs usually use defined binding sites to recognize and directly interact with their target RNA molecule. Individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) experiments are an important tool to de- scribe such interactions in cell cultures in-vivo. This experimental protocol yields millions of individual sequencing reads from which the binding spec- trum of the RBP under study can be deduced. In this PhD thesis I studied how RNA processing is driven from RBP binding by analyzing iCLIP-derived sequencing datasets.
First, I described a complete data analysis pipeline to detect RBP binding sites from iCLIP sequencing reads. This workflow covers all essential process- ing steps, from the first quality control to the final annotation of binding sites. I described the accurate integration of biological iCLIP replicates to boost the initial peak calling step while ensuring high specificity through replicate re- producibility analysis. Further I proposed a routine to level binding site width to streamline downstream analysis processes. This was exemplified in the re- analysis of the binding spectrum of the U2 small nuclear RNA auxiliary factor 2 (U2AF2, U2AF65). I recaptured the known dominance of U2AF65 to bind to intronic sequences of protein-coding genes, where it likely recognizes the polypyrimidine tract as part of the core spliceosome machinery.
In the second part of my thesis, I analyzed the binding spectrum of the serine and arginine rich splicing factor 6 (SRSF6) in the context of diabetes. In pancreatic beta-cells, the expression of SRSF6 is regulated by the transcription factor GLIS3, which encodes for a diabetes susceptibility gene. It is known that SRSF6 promotes beta-cell death through the splicing dysregulation of genes essential to beta-cell function and survival. However, the exact mechanism of how these RNAs are targeted by SRSF6 remains poorly understood. Here, I applied the defined iCLIP processing pipeline to describe the binding landscape of the splicing factor SRSF6 in the human pancreatic beta-cell line EndoC-H1. The initial binding sites definition revealed a predominant binding to coding sequences (CDS) of protein-coding genes. This was followed up by extensive motif analysis which revealed a so far, in human, unknown purine-rich binding motif. SRSF6 seemed to specifically recognize repetitions of the triplet GAA. I also showed that the number of contiguous triplets correlated with increasing binding site strength. I further integrated RNA-sequencing data from the same cell type, with SRSF6 in KD and in basal conditions, to analyze SRSF6- related splicing changes. I showed that the exact positioning of SRSF6 on alternatively spliced exons regulates the produced transcript isoforms. This mechanism seemed to control exons in several known susceptibility genes for diabetes.
In summary, in my PhD thesis, I presented a comprehensive workflow for the processing of iCLIP-derived sequencing data. I applied this pipeline on a dataset from pancreatic beta-cells to unveil the impact of SRSF6-mediated splicing changes. Thus, my analysis provides novel insights into the regulation of diabetes susceptibility genes.
Ribosome assembly is an essential and carefully choreographed cellular process. In eukaryotes, several 100 proteins, distributed across the nucleolus, nucleus, and cytoplasm, co-ordinate the step-wise assembly of four ribosomal RNAs (rRNAs) and approximately 80 ribosomal proteins (RPs) into the mature ribosomal subunits. Due to the inherent complexity of the assembly process, functional studies identifying ribosome biogenesis factors and, more importantly, their precise functions and interplay are confined to a few and very well-established model organisms. Although best characterized in yeast (Saccharomyces cerevisiae), emerging links to disease and the discovery of additional layers of regulation have recently encouraged deeper analysis of the pathway in human cells. In archaea, ribosome biogenesis is less well-understood. However, their simpler sub-cellular structure should allow a less elaborated assembly procedure, potentially providing insights into the functional essentials of ribosome biogenesis that evolved long before the diversification of archaea and eukaryotes. Here, we use a comprehensive phylogenetic profiling setup, integrating targeted ortholog searches with automated scoring of protein domain architecture similarities and an assessment of when search sensitivity becomes limiting, to trace 301 curated eukaryotic ribosome biogenesis factors across 982 taxa spanning the tree of life and including 727 archaea. We show that both factor loss and lineage-specific modifications of factor function modulate ribosome biogenesis, and we highlight that limited sensitivity of the ortholog search can confound evolutionary conclusions. Projecting into the archaeal domain, we find that only few factors are consistently present across the analyzed taxa, and lineage-specific loss is common. While members of the Asgard group are not special with respect to their inventory of ribosome biogenesis factors (RBFs), they unite the highest number of orthologs to eukaryotic RBFs in one taxon. Using large ribosomal subunit maturation as an example, we demonstrate that archaea pursue a simplified version of the corresponding steps in eukaryotes. Much of the complexity of this process evolved on the eukaryotic lineage by the duplication of ribosomal proteins and their subsequent functional diversification into ribosome biogenesis factors. This highlights that studying ribosome biogenesis in archaea provides fundamental information also for understanding the process in eukaryotes.
In recent years, the popularity of rock-climbing has grown tremendously, setting an increasing pressure on cliff habitats. Climbing may be particularly harmful in the Mediterranean biome due to its appropriate environmental conditions for climbing. A few studies have identified the effect of climbing on plant diversity at a small-scale (namely locally or even just in specific climbing areas). However, no studies exist assessing the potential risk of rock-climbing on a broad-scale (e.g., regional or national). The study aims to identify the priority locations and priority cliff plant species in Spain to focus future study efforts. Spain was selected because it is a plant biodiversity hotspot, with a great diversity of endemic and endangered species, and one of the most popular destinations for climbers. We used a geographic information system-based approach to model the spatial concurrence among Spanish climbing areas (and climbing intensity), natural protected areas (NPAs), and distribution of threatened cliff plants (and their IUCN threat category). We found that 53.5% of climbing areas in Spain are located within a NPA, most of them falling into NPAs of medium protection level. We mapped 151 threatened cliff plants, identifying four medium priority Mediterranean locations and eight priority species in which future research efforts should be focused. High-priority study locations are absent in Spain according to our spatial modeling. For the first time on a national scale, this study identifies areas in which climbing represents a potential threat for cliff habitats and threatened plants. These findings contribute to designing field studies on the effects of rock-climbing on Mediterranean cliffs, laying the groundwork for a sustainable, yet challenging, balance between the protection of these unique habitats and rock-climbing.
Octanoic acid (C8 FA) is a medium-chain fatty acid which, in nature, mainly occurs in palm kernel oil and coconuts. It is used in various products including cleaning agents, cosmetics, pesticides and herbicides as well as in foods for preservation or flavoring. Furthermore, it is investigated for medical treatments, for instance, of high cholesterol levels. The cultivation of palm oil plants has surged in the last years to satisfy an increasing market demand. However, concerns about extensive monocultures, which often come along with deforestation of rainforest, have driven the search for more environmentally friendly production methods. A biotechnological production with microbial organisms presents an attractive, more sustainable alternative.
Traditionally, the yeast Saccharomyces cerevisiae has been utilized by mankind in bread, wine, and beer making. Based on comprehensive knowledge about its metabolism and genetics, it can nowadays be metabolically engineered to produce a plethora of compounds of industrial interest. To produce octanoic acid, the cytosolic fatty acid synthase (FAS) of S. cerevisiae was utilized and engineered. Naturally, the yeast produces mostly long-chain fatty acids with chain lengths of C16 and C18, and only trace amounts of medium-chain fatty acids, i.e. C8-C14 fatty acids. To generate an S. cerevisiae strain that produces primarily octanoic acid, a mutated version of the FAS was generated (Gajewski et al., 2017) and the resulting S. cerevisiae FASR1834K strain was utilized in this work as a starting strain.
The goal of this thesis was to develop and implement strategies to improve the production level of this strain. The current mode of quantification of octanoic acid includes labor-intensive, low-throughput sample preparation and measurement – a main obstacle in generating and screening for improved strain variants. To this end, a main objective of this thesis was the development of a biosensor. The biosensor was based on the pPDR12 promotor, which is regulated by the transcription factor War1. Coupling pPDR12 to GFP as the reporter gene on a multicopy plasmid allowed in vivo detection via fluorescence intensity. The developed biosensor enabled rapid and facile quantification of the short- and medium-chain fatty acids C6, C7 and C8 fatty acids (Baumann et al., 2018). This is the first biosensor that can quantify externally supplied octanoic acid as well as octanoic acid present in the culture supernatant of producer strains with a high linear and dynamic range. Its reliability was validated by correlation of the biosensor signal to the octanoic acid concentrations extracted from culture supernatants as determined by gas chromatography. The biosensor’s ability to detect octanoic acid in a linear range of 0.01-0.75 mM (≈1-110 mg/L), which is within the production range of the starting strain, and a response of up to 10-fold increase in fluorescence after activation was demonstrated.
A high-throughput FACS (fluorescence-activated cell sorting) screening of an octanoic acid producer strain library was performed with the biosensor to detect improved strain variants (Baumann et al., 2020a). For this purpose, the biosensor was genomically integrated into an octanoic acid producer strain, resulting in drastically reduced single cell noise. The additional knockout of FAA2 successfully prevented medium-chain fatty acid degradation. A high-throughput screening protocol was designed to include iterative enrichment rounds which decreased false positives. The functionality of the biosensor on single cell level was validated by adding octanoic acid in the range of 0-80 mg/L and subsequent flow cytometric analysis. The biosensor-assisted FACS screening of a plasmid overexpression library of the yeast genome led to the detection of two genetic targets, FSH2 and KCS1, that in combined overexpression enhanced octanoic acid titers by 55 % compared to the parental strain. This was the first report of an effect of FSH2 and KCS1 on fatty acid titers. The presented method can also be utilized to screen other genetic libraries and is a means to facilitate future engineering efforts.
In growth tests, the previously reported toxicity of octanoic acid on S. cerevisiae was confirmed. Different strategies were harnessed to create more robust strains. An adaptive laboratory evolution (ALE) experiment was conducted and several rational targets including transporter- (PDR12, TPO1) and transcription factor-encoding genes (PDR1, PDR3, WAR1) as well as the mutated acetyl-CoA carboxylase encoding gene ACC1S1157A were overexpressed or knocked out in producer or non-producer strains, respectively. Despite contrary previous reports for other strain backgrounds, an enhanced robustness was not observable. Suspecting that the utilized laboratory strains have a natively low tolerance level, four industrial S. cerevisiae strains were evaluated in growth assays with octanoic acid and inherently more robust strains were detected, which are suitable future production hosts.
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