Biology subjects

Schlueter, D.

Publications and source records attributed to Schlueter, D..

5 recordsLinked to original sources

bioRxiv2026

OTUB1 controls marginal zone B-cell development by stabilizing RelA in a CD40-dependent manner

Ubiquitin-dependent regulation of NF-{kappa}B signaling is essential for B-cell homeostasis and fate decisions, yet the contribution of specific deubiquitinating enzymes remains incompletely defined. OTUB1, a lysine-48-specific deubiquitinase, has been broadly implicated in immune regulation, including control of NF-{kappa}B signaling and prevention of immune hyperactivation. Previous studies have demonstrated that B cell-specific deletion of OTUB1 leads to B cell hyperplasia, increased antibody production, and lupus-like autoimmunity, highlighting its importance in maintaining B cell tolerance and immune homeostasis. Using B cell-specific OTUB1-deficient mice, we show that loss of OTUB1 leads to a marked expansion of marginal zone (MZ) B cells and their precursor populations in the spleen, accompanied by an activated phenotype and enhanced proliferative responses, particularly upon CD40 stimulation. OTUB1 deficiency results in altered CD40-induced NF-{kappa}B signaling, characterized by enhanced I{kappa}B degradation and increased nuclear accumulation of p50-containing NF-{kappa}B complexes, despite reduced RelA stability. Mechanistically, we show that OTUB1 interacts with RelA, restricting its lysine-48-linked ubiquitination and proteasomal degradation, thereby stabilizing this key transcription factor. Collectively, these findings identify RelA as a novel OTUB1 target and uncover an additional layer of ubiquitin-dependent control of NF-{kappa}B signaling that governs splenic B-cell homeostasis and marginal zone B-cell development.

immunology↗

bioRxiv2026

Deletion of OTUD7B in astrocytes protects against cerebral malaria by inhibiting microvesicle-induced TRAF3/TRAF6-mediated neuroinflammation

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Damage of the blood-brain barrier (BBB) and endothelial dysfunction are established drivers of the disease pathology, however, whether astrocytes, a major constituent of the BBB, influence the disease outcome remains unclear. Using the murine model of experimental cerebral malaria (ECM), we show that astrocytes decisively regulate the outcome of ECM and the deubiquitinating enzyme OTUD7B in astrocytes fosters the disease. Mice lacking astrocytic OTUD7B showed reduced brain pathology and were protected from ECM compared with wildtype littermate controls. Transcriptomic profiling of ex vivo-isolated astrocytes revealed reduced proinflammatory chemokines and cytokines in the absence of OTUD7B. Plasmodium infection-associated microvesicles triggered a pro-inflammatory response in astrocytes, which was dependent on OTUD7B. Mechanistically, OTUD7B cleaved K48-linked ubiquitin chains from TRAF3 and TRAF6 upon stimulation with microvesicles or activation of TLR3/TLR9 by plasmodial nucleic acids. The OTUD7B-dependent TRAF3 and TRAF6 stabilization led to sustained NF-{kappa}B and p38 MAP kinase signaling and CXCL10 expression. Therapeutic silencing of CNS Otud7b or Cxcl10 expression after disease onset protected mice from ECM, identifying the cerebral OTUD7B-Cxcl10 axis as an attractive therapeutic target.

immunology↗

bioRxiv2025

Metabolites produced by gut bacteria under anoxic conditions drive the suppression of Acinetobacter baumannii

Multidrug-resistant (MDR) bacteria pose a significant global health threat. Among these, Acinetobacter baumannii, particularly carbapenem-resistant A. baumannii, is a leading cause of healthcare-associated infections. Emerging evidence links gut colonization to systemic infections, highlighting opportunities for new control strategies. We demonstrate that A. baumannii can survive under anaerobic conditions ([≤]1%) and shows limited growth under low oxygen conditions ([≥]1%), underscoring its adaptation to niches in the intestine. However, specific carbohydrates, including maltose, provide the gut bacteria Klebsiella oxytoca with a competitive advantage under anoxic conditions, enabling it to actively suppress A. baumannii through its metabolism. Notably, maltose induces this suppressive capacity in other commensals and complex gut microbiomes as well. Force-feeding experiments in Galleria mellonella larvae corroborate that K. oxytoca in combination with maltose significantly reduces A. baumannii recovery in gut environments. These findings suggest that targeted carbohydrate supplementation could enhance probiotic strategies, creating an environment unfavorable to A. baumannii.

microbiology↗

bioRxiv2024

The deubiquitinating enzyme CYLD impairs NF-κB- and STAT1-dependent macrophage intrinsic immunity to Staphylococcus aureus

In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus (S.) aureus, contributing to the severity and clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a type 2 inflammatory signature, including M2 macrophages, which cannot eradicate S. aureus. Since S. aureus is effectively controlled in macrophages activated by pattern recognition receptor (PRR)-induced NF-{kappa}B and interferon (IFN)-{gamma}-induced STAT1 stimulation, we hypothesized that pre-treatment with LPS as a PRR/TLR4-activating agent and IFN-{gamma} would induce effective control of S. aureus in monocyte-derived macrophages (MDMs) of AD patients. Our data show that the deubiquitinating enzyme CYLD is strongly expressed in skin macrophages and MDMs from AD patients compared to healthy controls and impairs the anti-staphylococcal activity of PRR-activated and IFN-treated MDMs. Functionally, CYLD impaired M1 macrophage polarization, as evidenced by reduced expression of CD80, TNF, and IL-6 upon LPS- and IFN-{gamma} treatment in CYLD-deficient as compared to wild-type (WT) MDM/THP1 macrophages. Mechanistically, CYLD inhibited IFN-{gamma}-induced STAT1 phosphorylation and activation by binding to STAT1 and inducing its K63 deubiquitination. CYLD also interacted with TRAF6 and NEMO/IKK{gamma} in the MYD88 signaling pathway and with RIPK2 in the NOD2 pathway, leading to impaired activation of NF-{kappa}B. Inhibition of both STAT1 by siRNA and NF-{kappa}B by IKK inhibitor treatment, respectively, independently abolished the control of S. aureus in both CYLD-deficient and WT THP1 macrophages, which harbored identical high numbers of the pathogen. The in vivo inhibitory function of CYLD on the control of S. aureus was also observed upon infection of Cyld-deficient and WT mice. Collectively, these data illustrate that the increased expression of CYLD in macrophages of AD patients is a factor contributing to the ineffective control of S. aureus, diminishes M1 macrophage polarization, and that CYLD deletion unleashes the break on effective STAT1 and NF-{kappa}B-dependent control of S. aureus.

immunology↗

bioRxiv2022

Predicting butyrate- and propionate-forming bacteria of gut microbiota from sequencing data

BackgroundThe bacteria-derived short chain fatty acids (SCFAs) butyrate and propionate play important (distinct) roles in health and disease and understanding the ecology of respective bacteria on a community-wide level is a top priority in microbiome research. The aim of this study was to reveal members harboring main pathways for the production of those metabolites and assess the applicability of sequence data (metagenomics and 16S rRNA gene) to predict SCFAs production in vitro and in vivo. ResultsA clear split between butyrate- and propionate-forming bacteria was detected with only very few taxa exhibiting pathways for the production of both SCFAs. After in vitro growth of fecal communities from distinct donors (n=8) on different substrates (n=7) abundances of bacteria exhibiting pathways correlated with respective SCFA concentrations, in particular in the case of butyrate. While final growth differed markedly between cultures, communities showed high functional redundancies with comparable yields, i.e., concentration of metabolite per grown bacterium exhibiting pathway(s), irrespective of the donor and substrate used. For propionate, correlations were weaker indicating that its production is less imprinted into the core metabolism compared with butyrate-forming bacteria. Longitudinal measurements in vivo (five samples derived from 20 subjects) also revealed a correlation between abundances of pathway-carrying bacteria and concentrations of the two SCFAs. Additionally, lower bacterial cell concentrations, together with higher stool moisture, promoted overall bacterial activity (measured by flow cytometry and coverage patterns of metagenome-assembled genomes) that led to elevated SCFAs concentrations with over-proportional levels of butyrate. Butyrate concentrations displayed lower temporal stability than propionate, however, abundances of bacteria exhibiting the butyrate-forming pathway were more stable than those carrying pathways for propionate production. Predictions on pathway abundances based on 16S rRNA gene data using our in-house database worked well yielding similar results as metagenomic-based analyses. ConclusionsWe demonstrated that pathway abundances enable predictions on concentrations of SCFAs indicating that stimulating bacterial growth directly leads to more production of those compounds. The strong separation of gut microbiota into two functional communities facilitates the development of precision intervention strategies targeting either metabolite.

microbiology↗