Biology subjects

Steiner, K.

Publications and source records attributed to Steiner, K..

5 recordsLinked to original sources

bioRxiv2025

The Legionella effector RidL promotes mitochondrial fragmentation through phosphorylation activation of the large GTPase Drp1

Intracellular pathogens such as Legionella pneumophila secrete effector proteins that manipulate host cell processes to promote bacterial survival. One such effector, RidL, is known to inhibit retrograde trafficking by interacting with the retromer complex via its N-terminal domain. Here, we identify a second function of RidL mediated by its C-terminal domain, which directly binds to the mitochondrial fission GTPase Drp1 and related large GTPases. In vitro, RidL reduces Drp1 GTPase activity and disrupts its oligomerization. During infection, RidL localizes to mitochondria, enhances the accumulation of Drp1 and the outer membrane protein Tom20, and impairs mitochondrial dynamics and function. Moreover, in L. pneumophila-infected cells, RidL promotes phosphorylation of Drp1 at Ser616, leading to Drp1 activation and mitochondrial fragmentation. These findings establish RidL as a bifunctional effector that targets both the retromer complex and Drp1 through distinct domains. By interfering with host mitochondrial dynamics, RidL enables L. pneumophila to remodel host organelles and optimize conditions for intracellular replication.

microbiology↗

bioRxiv2025

Structure and function of a fungal AB toxin-like chimerolectin involved in anti-nematode defense

Fungal defense against predators largely relies on protein toxins, many of which are lectins. We previously showed that the production of the nematotoxin CCTX2 is upregulated in the Agaricomycete Coprinopsis cinerea upon predation by nematodes. Here, we classify CCTX2 as the founding member of a family of fungal chimerolectins. Cryo-EM analysis to 3.2 [A] resolution reveals five domains. The four N-terminal {beta}-trefoil fold (BTF) domains cradle a C-terminal domain, which exhibits a novel +{beta} protein fold. Mutational analysis shows that both N-terminal and C-terminal domains are required for nematotoxicity. While the biochemical function of the C-terminal domain remains unclear, the first two BTF domains enable CCTX2 to bind to glycosphingolipids with LacNAc or LacdiNAc glycoepitopes on nematode intestinal epithelial cells. Experiments in the model nematode Caenorhabditis elegans demonstrate that the chimerolectin CCTX2 exploits the endocytic and retrograde trafficking machinery of the target cell to exert its toxicity and obtain access to the yet-to-be-identified intracellular target of the non-lectin domain. The structure and mode of action of CCTX2 is reminiscent of bacterial and plant AB toxins.

microbiology↗

bioRxiv2025

Role of Chloroplast Lipid-Remodelling Protein 23 During Cold Acclimation in Arabidopsis thaliana

Cold acclimation is a crucial physiological process that enables plants to adapt to low temperatures. A key aspect of this adaptation is lipid remodeling, which preserves membrane fluidity and integrity under cold stress. Proteins of the chloroplast envelope membranes are increasingly recognized for their role in acclimation to changing environmental conditions. While lipid synthesis occurs at the inner envelope membrane, little is known about specific proteins involved in lipid remodeling during cold acclimation. In this study, we investigate the role of Chloroplast Lipid Remodeling Protein 23 (CLRP23) as a component of the inner chloroplast envelope membrane. Subcellular fractionation combined with protease protection assays provided evidence for its orientation toward the intermembrane space. To explore its function, we analyzed the physiological performance and lipid composition in CLRP23-deficient mutant plants. Under cold stress, we observed significant impairments in photosynthesis and exaggerations in galactolipid response, suggesting CLRP23 is involved in lipid remodeling. Lipid overlay assays, supported by in silico docking analyses, demonstrate that CLRP23 can directly interact with chloroplast lipids, including galactolipids. Complementary transcriptomic and proteomic analyses reveal broader effects on cold-responsive pathways, supporting the view that CLRP23 contributes to the integration of membrane and metabolic responses during acclimation. These findings expand our understanding of protein-mediated processes during cold acclimation.

plant biology↗

bioRxiv2024

Targeting PI3K-gamma in myeloid driven tumour immune suppression: A Systematic Review and Meta-Analysis of the Preclinical Literature

The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), contribute to immune suppression in the TME 1,2. This poses a significant challenge for novel immunotherapeutics that rely on host immunity to exert their effect. This systematic review explores the preclinical evidence surrounding the inhibition of phosphoinositide 3-kinase gamma (PI3K{gamma}) as a strategy to reverse myeloid-driven immune suppression in solid tumours. EMBASE, MEDLINE, and PubMed databases were searched on 6th October 2022 using keyword and subject heading terms to capture relevant studies. The studies, focusing on PI3K{gamma} inhibition in animal models, were subjected to predefined inclusion and exclusion criteria. Extracted data included tumour growth kinetics, survival endpoints, and immunological responses which were meta-analysed. PRISMA and MOOSE guidelines were followed. A total of 36 studies covering 73 animal models were included in the review and meta-analysis. Tumour models covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head and neck, soft tissue, gastric, and oral cancer. The predominant PI3K{gamma} inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. Combination therapies, often involving chemotherapy, radiotherapy, immune checkpoint inhibitors, biological agents, or vaccines, were explored in 81% of studies. Analysis of tumour growth kinetics revealed a statistically significant though heterogeneous response to PI3K{gamma} monotherapy, whereas the tumour growth in combination treated groups were more consistently reduced. Survival analysis showed a pronounced increase in median overall survival with combination therapy. This systematic review provides a comprehensive analysis of preclinical studies investigating PI3K{gamma} inhibition in myeloid-driven tumour immune suppression. The identified studies underscore the potential of PI3K{gamma} inhibition in reshaping the TME by modulating myeloid cell functions. The combination of PI3K{gamma} inhibition with other therapeutic modalities demonstrated enhanced antitumor effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3K{gamma}-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/593156v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@cb6915org.highwire.dtl.DTLVardef@5fe73corg.highwire.dtl.DTLVardef@462cf3org.highwire.dtl.DTLVardef@1313b00_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Potential of genomic selection for improvement of resistance to Ostreid Herpes virus in Pacific oyster (Crassostrea gigas)

In genomic selection (GS), genome-wide SNP markers are used to generate genomic estimated breeding values (gEBVs) for selection candidates. The application of GS in shellfish looks promising and has the potential to help in dealing with one of the main issues currently affecting Pacific oyster production worldwide, which is the \"summer mortality syndrome\". This causes periodic mass mortality in farms worldwide and has mainly been attributed to a specific variant of the Ostreid herpesvirus (OsHV-1-var). In the current study, we evaluated the potential of genomic selection for host resistance OsHV in Pacific oysters, and compared it to pedigree-based approaches. An OsHV-1 disease challenge was performed using an immersion-based virus exposure treatment for oysters for seven days. 768 samples were genotyped using the medium density SNP array for oysters. GWAS was performed for the survival trait using a GBLUP approach in BLUPF90 software. Heritability ranged from 0.25{+/-}0.05 to 0.37{+/-}0.05 (mean{+/-}s.e) based on pedigree and genomic information, respectively. Genomic prediction was more accurate than pedigree prediction, and SNP density reduction had little impact on prediction accuracy until marker densities dropped below [~]500 SNPs. This demonstrates the potential for GS in Pacific oyster breeding programs and importantly, demonstrates that a low number of SNPs might suffice to obtain accurate gEBVs, thus potentially making the implementation of GS more cost effective.

genomics↗