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Krebs, M.

Publications and source records attributed to Krebs, M..

17 recordsLinked to original sources

A calcium-fingerprint atlas infers the signaling modes of complex elicitors and reveals a salt-like response to a humic biostimulant

A central challenge in plant signaling is to infer, from an observed response, the mechanism that produced it, including perception and signaling components involved. Cytosolic calcium (Ca2+) is well suited to this reverse-engineering problem: it is a universal early messenger whose spatiotemporal pattern, the Ca2+ signature, is shaped by the specific channels and receptors a stimulus activates. We hypothesize that multiparametric analysis of Ca2+ signals can identify the main signaling pathways activated by complex or poorly defined elicitors such as biostimulants. Here, we establish a quantitative framework to resolve Ca2+ dynamics in roots of Arabidopsis seedlings by transforming spatiotemporal Ca2+ transients into multidimensional signatures. Using a normalization and feature extraction approach (Crestline), we define descriptors capturing the onset time, location along the root axis, duration, and propagation of Ca2+ signals tip- or shootwards, enabling robust comparison across stimuli. Integration of these descriptors reveals stimulus-specific "calcium fingerprints" that allow systematic classification of responses to biotic and abiotic cues within a structured signaling space. To test whether projecting an uncharacterized input into this space can predict its signaling mode, we analyzed a complex humic biostimulant. Its response fell within the fast-onset region of signaling space shared by DAMP and salt responses, clearly apart from MAMP responses, and was altered in moca1, a mutant impaired in salt sensing. Together, these findings establish Ca2+ dynamics as an interpretable encoding layer for environmental information and provide a scalable framework to resolve complex biological inputs.

plant biology↗

A unified photosensitizer platform for in situ DNA, RNA, and protein directed proximity labeling

Cells depend on the spatial organization of proteins, RNA, and DNA into discrete subcellular compartments. Previous methods have largely centered on measuring spatial organization based on only one of these biomolecular classes at a time. Here, we demonstrate that POCA photocatalytic proximity labeling can serve as a unified photosensitizer-based platform for profiling the proximal proteomes of protein, RNA, and DNA targets within a single experimental framework. We show that POCA can harness standard immunofluorescence or in situ hybridization workflows to specifically target organic fluorophore photosensitizers to intracellular targets for proximity labeling in fixed cells. POCA-targeted proximity labeling requires minimal cellular input and does not require genetic engineering. Additionally, POCA photosensitizers are selected to also be fluorescent, enabling direct confirmation of on-target localization by imaging prior to proteomic analysis. To demonstrate broad utility, we apply POCA across multiple molecular targets spanning protein, RNA, and genomic DNA, including components of the nuclear pore complex, nucleolus, nuclear speckles, telomeres, and pericentromeric heterochromatin. By anchoring proximity labeling to both a protein and an RNA within the same nuclear compartment, we resolve shared and distinct proximal proteomes from orthogonal molecular perspectives.

cell biology↗

A narrow thermodynamic design window governs selective membrane permeabilization and antiviral activity of amphipathic peptides

Designing molecules that selectively target therapeutically relevant membranes, such as viral envelopes, while sparing host cells is challenging: these membranes closely resemble host bilayers, so selectivity must exploit subtle lipid composition and curvature differences and demands precise tuning of affinity and hydrophobicity, yet curated sequence-specificity data are scarce. Here we show that selective membrane permeabilization and membrane-selective activity of amphipathic peptides are governed by a narrow thermodynamic design window defined by membrane curvature affinity and molecular hydrophobicity. Using a physics-driven generative workflow combining evolutionary molecular dynamics and a transformer predictor (PMIpred), we systematically explored and thermodynamically mapped peptide sequence space de novo without reliance on natural templates or experimental training data. Across four design generations we synthesized and experimentally characterized 43 peptides. Mapping functional activity onto a low-dimensional free-energy landscape reveals a confined thermodynamic "sweet spot" separating weak membrane binding from excessive hydrophobic association and cytotoxicity. Peptides operating within this regime efficiently permeabilize model membranes while maintaining low cellular toxicity. Antiviral activity against Zika virus and HIV-1 emerges in the same region but depends sensitively on membrane lipid composition. Quantitative thermodynamic design rules emerge for membrane-active peptides, illustrating how low-dimensional free-energy landscapes can guide the engineering of selective interactions at soft-matter interfaces.

biophysics↗

Detection of Cytosolic Ion Concentrations by the Trans-Golgi Network/Early Endosome is Important for Salt Tolerance

Plant survival requires cellular sensing systems that detect and respond to nutrient and ion fluctuations. The ability to monitor and adjust solute concentrations is essential for managing environmental stresses, particularly salt stress, yet the molecular mechanisms underlying cellular ion sensing remain largely unknown. Here, we combine luminal pH measurements with mathematical modelling of ion transport to investigate the role of the Trans-Golgi Network/Early Endosome (TGN/EE) for cellular ion homeostasis. Our results demonstrate that cytosolic concentrations of Cl-, Na+ and K+ directly impact ion transport activity at the TGN/EE, thereby influencing luminal pH dynamics. Specifically, we find that the TGN/EE lumen becomes more alkaline when plants are exposed to elevated NaCl concentrations, indicating a previously unrecognised role for endomembrane pH regulation in salt stress responses. Furthermore, we demonstrate that TGN/EE ion transport mutants that fail to exhibit NaCl-induced alkalisation display hypersensitivity to Na+. These findings indicate that the translation of elevated cytosolic ion concentrations into TGN/EE luminal alkalisation, represents an important mechanism for conferring Na+ tolerance in plant cells.

plant biology↗

Salicylic Acid restricts cell elongation and induces changes of vacuolar morphology and pH

The phytohormone salicylic acid (SA) is a key factor to balance plant defence as well as growth and development. While its role in plant defence has been investigated for decades, regulation of plant growth and development has only come into focus recently. It has been demonstrated that SA application inhibits growth independently of the established Non-expressor of Pathogenesis Related (NPR) receptors. However, the underlying mechanism of this growth inhibition on the cellular level remains largely elusive. Here we show that SA restricts cell elongation and induces changes of vacuolar morphology and pH. Rapidly upon SA application we observe homotypic vacuole fusion and a significant increase in vacuolar pH. These changes seem to be independent of the phytohormone auxin which has been reported to crosstalk with SA. By increasing vacuolar pH, SA directly impacts basic cellular functions such as vesicle trafficking or nutrient storage, leading eventually to cell size restriction and limited growth. Our results demonstrate an NPR-independent mechanism to attenuate growth, potentially allowing free resources to be relocated to withstand environmental stresses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/611645v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@af7652org.highwire.dtl.DTLVardef@1813f64org.highwire.dtl.DTLVardef@68e2e8org.highwire.dtl.DTLVardef@92a13_HPS_FORMAT_FIGEXP M_FIG C_FIG Salicylic Acid (SA) triggers a reduction in cell size and leads to a spherical vacuolar phenotype. This morphological change is accompanied by an increase in vacuolar pH, potentially due to the enhanced activity of a glycosylated SA (SAG) H+-antiporter and/or the inhibition of V-ATPase activity. In addition, SA disrupts the polarity of PIN2 auxin transporters, resulting in their uniform distribution across the cell membrane.

plant biology↗

DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci

The accuracy of crucial nuclear processes such as transcription, replication, and repair, depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed "DNA O-MAP", which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with label-free or sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-proximal proteins and DNA-DNA interactions at specific genomic loci. Furthermore, we establish that DNA O-MAP is applicable to both repetitive and unique genomic loci of varying sizes, from kilobase HOX gene clusters to megabase alpha-satellite repeats, and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.

systems biology↗

ATG8 delipidation is dispensable for plant autophagy

Intracellular recycling via autophagy is governed by post-translational modifications of the autophagy-related (ATG) proteins. One notable example is ATG4-dependent delipidation of ATG8, a process that plays critical but distinct roles in autophagosome formation in yeast and mammals. Here, we aimed to elucidate the specific contribution of this process to autophagosome formation in species representative of evolutionary distant green plant lineages: unicellular green alga Chlamydomonas reinhardtii, with a relatively simple set of ATG genes, and a vascular plant Arabidopsis thaliana, harboring expanded ATG gene families. Remarkably, the more complex autophagy machinery of Arabidopsis rendered ATG8 delipidation entirely dispensable for the maturation of autophagosomes, autophagic flux and related stress tolerance; whereas autophagy in Chlamydomonas strictly depended on the ATG4-mediated delipidation of ATG8. Importantly, we uncovered the distinct impact of different Arabidopsis ATG8 orthologs on autophagosome formation, especially prevalent under nitrogen depletion, providing a new insight into potential drivers behind the expansion of the ATG8 family in higher plants. Our findings underscore the evolutionary diversification of the molecular mechanism governing the maturation of autophagosomes in eukaryotic lineages and highlight how this conserved pathway is tailored to diverse organisms.

plant biology↗

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

Sample recruitment for research consortia, hospitals, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies systematically, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH consortium dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied both by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can modestly bias association tests and reduce predictive utility of polygenic scores. This is the largest, most comprehensive comparison of data integration approaches in the context of a large psychiatric biobank.

bioinformatics↗

Visual Clustering of Transcriptomic Data from Primary and Metastatic Tumors: Dependencies and Novel Pitfalls

Personalized Oncology is a rapidly evolving area and offers cancer patients therapy options more specific than ever. Yet, there is still a lack of understanding regarding transcriptomic similarities or differences of metastases and corresponding primary sites. Applying two unsupervised dimension reduction methods (t-Distributed Stochastic Neighbor Embedding (t-SNE) and Uniform Manifold Approximation Projection (UMAP)) on three datasets of metastases (n=682 samples) with three different data transformations (unprocessed, log10 as well as log10+1 transformed values), we visualized potential underlying clusters. Additionally, we analyzed two datasets (n=616 samples) containing metastases and primary tumors of one entity, to point out potential familiarities. Using these methods, no tight link between site of resection and cluster formation outcome could be demonstrated, neither for datasets consisting of solely metastasis nor mixed datasets. Instead, dimension reduction methods and data transformation significantly impacted visual clustering results. Our findings strongly suggest data transformation to be considered as another key element in interpretation of visual clustering approaches along with initialization and different parameters. Furthermore, the results indicate only minor transcriptional differences for metastases and corresponding primary tumors.

cancer biology↗

Glucose intolerance in aging is mediated by the Gpcpd1-GPC metabolic axis

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, muscle mediated metabolic homeostasis is perturbed, contributing to the onset of multiple chronic diseases. Our knowledge on the mechanisms responsible for this age-related perturbation is limited, as it is difficult to distinguish between correlation and causality of molecular changes in muscle aging. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is a highly abundant muscle enzyme responsible for the hydrolysis of the lipid glycerophosphocholine (GPC). The physiological function of GPCPD1 remained largely unknown. Here, we report that the GPCPD1-GPC metabolic pathway is dramatically perturbed in the aged muscle. Muscle-specific inactivation of Gpcpd1 resulted in severely affected glucose metabolism, without affecting muscle development. This pathology was muscle specific and did not occur in white fat-, brown fat- and liver-deficient Gpcpd1 deficient mice. Moreover, in the muscle specific mutant mice, glucose intolerance was markedly accelerated under high sugar and high fat diet. Mechanistically, Gpcpd1 deficiency results in accumulation of GPC, without any other significant changes in the global lipidome. This causes an "aged-like" transcriptomic signature in young Gpcpd1 deficient muscles and impaired insulin signaling. Finally, we report that GPC levels are markedly perturbed in muscles from both aged humans and patients with Type 2 diabetes, with a high correlation between GPC levels and increased chronological age. Our findings show the novel and critical physiological function of GPCPD1-GPC metabolic pathway to glucose metabolism, and the perturbation of this pathway with aging, which may contribute to glucose intolerance in aging.

physiology↗

CLCd and CLCf act redundantly at the TGN/EE and prevent acidification of the Golgi stack

The trans-Golgi network/early endosome (TGN/EE) serves as the central hub in which exo- and endocytic trafficking pathways converge and specificity of cargo routing needs to be achieved. Acidification is a hallmark of the TGN/EE and is maintained by the vacuolar H+-ATPase (V-ATPase) with support of proton-coupled antiporters. We show here that CLCd and CLCf, two distantly related members of the Arabidopsis chloride channel (CLC)-family that colocalize in the TGN/EE act redundantly and are essential for male gametophyte development. Combining an inducible knock-down approach and in vivo pH-measurements, we show here that reduced CLC-activity does not affect pH in the TGN/EE but causes accumulation of the V-ATPase in trans-Golgi cisternae leading to their hyper-acidification. Taken together, our results show that CLC-mediated anion transport into the TGN/EE is essential and affects spatio-temporal aspects of TGN/EE-maturation as well as its functional separation from the Golgi stack.

plant biology↗

Pharmacological and genetic manipulations of Ca2+ signaling have contrasting effects on auxin-regulated trafficking

A large part of a plants developmental plasticity relies on the activities of the phytohormone auxin and the regulation of its own distribution. This process involves a cohort of transcriptional and non-transcriptional effects of auxin on polar auxin transport, regulating the abundancy, biochemical activity and polar localization of the molecular components, predominantly PIN auxin exporters. While the transcriptional auxin signaling cascade has been well characterized, the mechanism and role of non-transcriptional auxin signaling remains largely elusive. Here, we addressed the potential involvement of auxin-induced Ca2+ signaling in auxins inhibitory effect on PIN endocytic trafficking. On the one hand, exogenous manipulations of Ca2+ availability and signaling effectively antagonized auxin effects suggesting that auxin-induced Ca2+ signaling is required for inhibition of internalization. On the other hand, we addressed the auxin-mediated inhibition of PIN internalization in the auxin signaling (tir1afb2,3) or Ca2+ channel (cngc14) mutants. These mutants were strongly defective in auxin-triggered Ca2+ signaling, but not in auxin-inhibited internalization. These data imply that, while Ca2+ signaling may be required for normal PIN trafficking, auxin-mediated increase in Ca2+ signaling is not a direct part of a downstream mechanism that mediates auxin effects on Brefeldin A-visualized PIN intercellular aggregation. These contrasting results obtained by comparing the mutant analysis versus the exogenous manipulations of Ca2+ availability and signaling illustrate the critical importance of genetics to unravel the role of Ca2+ in a process of interest.

cell biology↗

The Arabidopsis V-ATPase is localized to the TGN/EE via a seed plant specific motif and acts in a partially redundant manner with the tonoplast enzyme

Vacuolar-type H+-ATPases (V-ATPases) are versatile proton pumps that control the pH of many intracellular compartments in all eukaryotic cells. The localization of the Arabidopsis V-ATPase was previously shown to be determined by the isoforms of subunit a (VHA-a). The incorporation of VHA-a1 targets the V-ATPase to the trans-Golgi network/early endosome (TGN/EE) whilst the incorporation of VHA-a2 or VHA-a3 targets the V-ATPase to the tonoplast. By employing chimeric proteins and site directed mutagenesis we identified a targeting domain (a1-TD) containing an acidic cluster in the N-terminus of VHA-a1 that serves as both an ER export signal and as a TGN retention motif. The a1-TD is conserved among seed plants and we confirmed experimentally that its presence is predictive of TGN/EE- localization. In contrast to many other non-seed plants, the liverwort Marchantia polymorpha encodes only a single VHA-a subunit (MpVHA-a) and we show here that it is predominantly localized at the tonoplast. In our attempts to determine if MpVHA-a can functionally replace the Arabidopsis VHA-a isoforms, we used CRISPR/Cas9 to generate null-alleles lacking VHA-a1 and discovered that its function is essential for male gametophyte development but can be replaced by VHA-a2 and VHA-a3 during vegetative growth.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗

Axenic in-vitro cultivation of nineteen peat-moss (Sphagnum L.) species as a resource for basic biology, biotechnology and paludiculture

O_LIThe cultivation of Sphagnum mosses reduces CO2 emissions by rewetting drained peatlands and by substituting peat with renewable biomass. Sphagnum farming requires large volumes of founder material, which can only be supplied sustainably by axenic cultivation in bioreactors. C_LIO_LIWe established axenic in-vitro cultures from sporophytes of 19 Sphagnum species collected in Austria, Germany, Latvia, Netherlands, Russia and Sweden, namely S. angustifolium, S. balticum, S. capillifolium, S. centrale, S. compactum, S. cuspidatum, S. fallax, S. fimbriatum, S. fuscum, S. lindbergii, S. medium/divinum, S. palustre, S. papillosum, S. rubellum, S. russowii, S. squarrosum, S. subnitens, S. subfulvum, and S. warnstorfii. These species cover five of the six European Sphagnum sections, namely Acutifolia, Cuspidata, Rigida, Sphagnum and Squarrosa. C_LIO_LITheir growth was measured in axenic suspension cultures, whereas their ploidy was determined by flow cytometry and compared with the genome size of Physcomitrella patens. We identified haploid and diploid Sphagnum species, found that their cells are predominantly arrested in the G1-phase of the cell cycle, and did not find a correlation between plant productivity and ploidy. C_LIO_LIWith this collection, high-quality founder material for diverse large-scale applications but also for basic Sphagnum research is available from the International Moss Stock Center (IMSC). C_LI

plant biology↗

Pathogen-induced pH changes regulate the growth-defense balance of plants

Environmental adaptation of organisms relies on fast perception and response to external signals, which lead to developmental changes. Plant cell growth is strongly dependent on cell wall remodeling. However, little is known about cell wall-related sensing of biotic stimuli and the downstream mechanisms that coordinate growth and defense responses. We generated genetically encoded pH sensors to determine absolute pH changes across the plasma membrane in response to biotic stress. A rapid apoplastic acidification by phosphorylation-based proton pump activation was followed by an acidification of the cortical side of the plasma membrane in response to the fungus Fusarium oxysporum. The proton chemical gradient modulation immediately reduced cellulose synthesis and cell growth and, furthermore, had a direct influence on the pathogenicity of the fungus. All these effects were dependent on the COMPANION OF CELLULOSE SYNTHASE proteins that are thus at the nexus of plant growth and defense. Hence, our discoveries show a remarkable connection between plant biomass production, immunity, and pH control, and advance our ability to investigate the plant growth-defense balance.

plant biology↗

Pyrophosphate modulates stress responses via SUMOylation

Pyrophosphate (PPi), a byproduct of macromolecule biosynthesis is maintained at low levels by soluble inorganic pyrophosphatases (sPPase) found in all eukaryotes. In plants, H+-pumping pyrophosphatases (H+-PPase) convert the substantial energy present in PPi into an electrochemical gradient. We show here, that both cold- and heat stress sensitivity of fugu5 mutants lacking the major H+-PPase isoform AVP1 is caused by reduced SUMOylation. In addition, we show that increased PPi concentrations interfere with SUMOylation in yeast and we provide evidence that SUMO activating E1-enzymes are inhibited by micromolar concentrations of PPi in a non-competitive manner. Taken together, our results do not only provide a mechanistic explanation for the beneficial effects of AVP1 overexpression in plants but they also highlight PPi as an important integrator of metabolism and stress tolerance.

biochemistry↗

Fine-tuning of ABA responses by the protein kinase WNK8

The phytohormone abscisic acid (ABA) regulates various growth- and developmental processes in response to limiting water conditions. ABA functions through an established signaling pathway consisting of PYR1/PYL/RCAR ABA receptors that inhibit group A type 2C protein phosphatases (PP2Cs) in an ABA-dependent manner. Inhibition of PP2Cs enables the activation of SnRK2-type protein kinases that phosphorylate downstream targets including transcription factors and ion channels. However, ABA-dependent signals have to be integrated into other growth- and developmental programs to ensure a successful life cycle. Here, we have characterized the role of the protein kinase WNK8 in the ABA signalling pathway. Two T-DNA insertion alleles wnk8-1 and wnk8-4 exhibited contrasting ABA responses during seed germination and young seedling growth. However, reciprocal crossings with wild type plants suggested that wnk8-1 that still expressed the WNK8 kinase domain functioned in a hypermorphic and dominant manner. WNK8 directly interacted with the PP2C PP2CA in planta and was negatively regulated by this phosphatase in vitro. WNK8 also phosphorylated the ABA receptor PYR1 in vitro. Double mutant analyses revealed that the dominant allele wnk8-1 suppressed the ABA- and glucose hypersensitivity of the pp2ca-1 T-DNA allele. In transient protoplast assays WNK8 suppressed ABA-induced reporter gene expression that was dependent on a functional kinase. In summary, we have identified the protein kinase WNK8 as a negative regulator of ABA responses during young seedling establishment through its direct interaction with core ABA signaling components.\n\nSIGNIFICANCE STATEMENTThe phytohormone abscisic acid regulates the water household of plants through a defined core signaling pathway. Here we have identified the protein kinase WNK8 as a direct interactor of core abscisic acid signalling components and as a negative modulator of abscisic acid responses during young seedling development in Arabidopsis.

plant biology↗