Biology subjects

Schmid, E.

Publications and source records attributed to Schmid, E..

10 recordsLinked to original sources

bioRxiv2026

Microbiota-specific serum IgG links gut and joints through immune-endothelial crosstalk in arthritis

Rheumatoid arthritis (RA) pathogenesis involves early gut immune alterations that precede clinical onset and systemic bone involvement. Using mouse and human imaging mass cytometry (IMC) and tissue sequencing, this study shows that intestinal endothelial and immune changes emerge before or coincide with arthritis symptom development. In the collagen-induced arthritis (CIA) model, intestinal vascular permeability and endothelial gene activation promoting leukocyte trafficking appeared prior to synovial inflammation. Spatial mapping of murine and human ileal tissues predicted enhanced epithelial-immune interactions and lymphoid activation, suggesting mucosal immune priming before joint pathology. Both gut-selective 4{beta}7 integrin blockade with vedolizumab and endothelial barrier enhancement by imatinib significantly reduced arthritis severity in CIA mice. After clinical onset, microbiota-specific IgG responses expanded to recognize rare gut bacteria, reflecting increased microbial exposure. Bone marrow endothelium exhibited interferon-I-driven inflammation and vascular activation, indicating tissue-specific endothelial dysfunction. Microbiota-reactive IgG increased during CIA - likely a response to translocating gut bacteria and immune cell activation. Integrating mouse and human data, these findings define a mechanistic framework where endothelial barrier impairment, microbial translocation, and systemic endothelial activation initiate RA autoimmunity, revealing endothelial and mucosal pathways as targets for early intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/702529v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1ef2f41org.highwire.dtl.DTLVardef@77d66org.highwire.dtl.DTLVardef@1b9e4cborg.highwire.dtl.DTLVardef@15bd170_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Proteome-wide in silico screening for human protein-protein interactions

Protein-protein interactions (PPIs) drive virtually all biological processes, yet most PPIs have not been identified and even more remain structurally unresolved. We developed a two-step computational screen for human PPIs. First, a classifier called KIRC (Knowledge-Informed Rapid Classifier), trained on biological features, was used to rank all 200 million possible protein pairs in the human proteome by their interaction likelihood. Second, the [~]1.6 million top-ranked KIRC pairs were subjected to structure prediction by AlphaFold-Multimer and ranked using SPOC (Structure Prediction and Omics Classifier), which identifies functional predictions based on biological and structural features. This pipeline revealed 16,000 high-confidence PPIs ([~]90% precision), of which more than 5,000 were not previously recognized and more than 12,000 have not been structurally resolved. We use this "predictome" to formulate new hypotheses in different areas of biology, reinterpret low-resolution cryo-EM maps, and identify and validate novel PPIs that may support replication-coupled chromatin assembly. The predicted PPIs, viewable at predictomes.org, are expected to accelerate characterization of the molecular interactions that underlie vertebrate cell physiology.

bioinformatics↗

bioRxiv2025

Structure and function of IWS1 in transcription elongation

Transcription elongation by RNA polymerase II is a tightly regulated process that requires coordinated interactions between transcription elongation factors. IWS1 (Interacts with SPT6) has been implicated as a core elongation factor, but its molecular role remains unclear. We show that the intrinsically disordered C-terminal region of IWS1 contains short linear motifs (SLiMs) that multivalently engage the elongation machinery. Using cryo-electron microscopy, we map SLiMs in IWS1 that interact with Pol II subunits RPB1, RPB2, and RPB5, as well as elongation factors DSIF, SPT6, and ELOF1. Functional assays demonstrate that distinct IWS1 SLiMs specify IWS1 recruitment and IWS1-dependent transcription stimulation. IWS1 recruitment to the transcription elongation complex depends on association via the RPB1 jaw and binding of downstream DNA. Transcription elongation stimulation requires interactions with the RPB2 lobe and ELOF1. We identify other transcription elongation factors including ELOA and RECQL5 that bind the RPB1 jaw and demonstrate that IWS1 protects the activated transcription elongation complex from RECQL5 inhibition. We also reveal the binding of the histone reader and IWS1 interactor LEDGF to a transcribed downstream nucleosome. Our findings establish IWS1 as a modular scaffold that helps organize the transcription elongation complex, illustrating how disordered regions regulate transcription elongation.

molecular biology↗

bioRxiv2025

The aPBP-type cell wall synthase PBP1b plays a specialized role in fortifying the Escherichia coli division site against osmotic rupture

A multi-protein system called the divisome promotes bacterial division. This apparatus synthesizes the peptidoglycan (PG) cell wall layer that forms the daughter cell poles and protects them from osmotic lysis. In the model Gram-negative bacterium Escherichia coli, PG synthases called class A penicillin-binding proteins (aPBPs) have been proposed to play crucial roles in division. However, there is limited experimental support for aPBPs playing a specialized role in division that is distinct from their general function in the expansion and fortification of the PG matrix. Here, we present in situ cryogenic electron tomography data indicating that the aPBP-type enzyme PBP1b is required to produce a wedge-like density of PG at the division site. Furthermore, atomic force and live cell microscopy showed that loss of this structure weakens the division site and renders it susceptible to lysis. Surprisingly, we found that the lipoprotein activator LpoB needed to promote the general function of PBP1b was not required for normal division site architecture or its integrity. Additionally, we show that of the two PBP1b isoforms produced in cells, it is the one with an extended cytoplasmic N-terminus that functions in division, likely via recruitment by the FtsA component of the divisome. Altogether, our results demonstrate that PBP1b plays a specialized, LpoB-independent role in E. coli cell division involving the biogenesis of a PG structure that prevents osmotic rupture. The conservation of aPBPs with extended cytoplasmic N-termini suggests that other Gram-negative bacteria may use similar mechanisms to reinforce their division site.

microbiology↗

bioRxiv2025

Mucosal innate immune activation as the trigger to Prevotella species-induced arthritis in genetically resistant mice

An altered gut microbiota, particularly the expansion of Prevotellaceae members, is increasingly implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms hind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces a 100% arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11bCD11c myeloid cells, facilitating Th17 differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMV) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an IL-6-dependent manner. Similar changes with increase in innate immune cell activation and IL-6 levels were shown in gut biopsies from new-onset RA patients. The transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the hightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/643707v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ce227corg.highwire.dtl.DTLVardef@3a2d0eorg.highwire.dtl.DTLVardef@16404b6org.highwire.dtl.DTLVardef@1717dc1_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIColonization with Paleniella intestinalis bypasses genetic resistance, consistently inducing arthritis incidence in non-susceptible C57BL/6 mice C_LIO_LIP. intestinalis activates colonic CD11b+CD11c+ myeloid cells, driving systemic Th17 cell differentiation C_LIO_LIIn vitro, outer membrane vesicles from P. intestinalis or RA-derived S. copri RPC01 primed DCs that drive Th17 differentiation in an IL-6-dependent manner C_LIO_LITransfer of P. intestinalis-primed DCs or its outer membrane vesicles alone increases arthritis incidence in non-susceptible C57BL/6 mice C_LI

immunology↗

bioRxiv2024

USP37 prevents premature disassembly of stressed replisomes by TRAIP

The E3 ubiquitin ligase TRAIP associates with the replisome and helps this molecular machine deal with replication stress. Thus, TRAIP promotes DNA inter-strand crosslink repair by triggering the disassembly of CDC45-MCM2-7-GINS (CMG) helicases that have converged on these lesions. However, disassembly of single CMGs that have stalled temporarily would be deleterious, suggesting that TRAIP must be carefully regulated. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. We further show that TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37s response to topological stress. In conclusion, we propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.

molecular biology↗

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2023

NOP16 is a histone mimetic that regulates Histone H3K27 methylation and gene repression

Post-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3. NOP16 knockout selectively globally increases H3K27me3, a heterochromatin mark, without altering methylation of H3K4, H3K9, or H3K36 or acetylation of H3K27. NOP16 is overexpressed and linked to poor prognosis in breast cancer. Depletion of NOP16 in breast cancer cell lines causes cell cycle arrest, decreases cell proliferation and selectively decreases expression of E2F target genes and of genes involved in cell cycle, growth and apoptosis. Conversely, ectopic NOP16 expression in triple negative breast cancer cell lines increases cell proliferation, cell migration and invasivity in vitro and tumor growth in vivo, while NOP16 knockout or knockdown has the opposite effect. Thus, NOP16 is a histone mimic that competes with Histone H3 for H3K27 methylation and demethylation. When it is overexpressed in cancer, it derepresses genes that promote cell cycle progression to augment breast cancer growth.

cancer biology↗

bioRxiv2021

enviLink: A database linking contaminant biotransformation rules to enzyme classes in support of functional association mining

MotivationThe ability to assess and engineer biotransformation of chemical contaminants present in the environment requires knowledge on which enzymes can catalyze specific contaminant biotransformation reactions. For the majority of over 100000 chemicals in commerce such knowledge is not available. Enumeration of enzyme classes potentially catalyzing observed or de novo predicted contaminant biotransformation reactions can support research that aims at experimentally uncovering enzymes involved in contaminant biotransformation in complex natural microbial communities. DatabaseenviLink is a new data module integrated into the enviPath database and contains 316 theoretically derived linkages between generalized biotransformation rules used for contaminant biotransformation prediction in enviPath and 3rd level EC classes. Rule-EC linkages have been derived using two reaction databases, i.e., Eawag-BBD in enviPath, focused on contaminant biotransformation reactions, and KEGG. 32.6% of identified rule-EC linkages overlap between the two databases, whereas 40.2% and 27.2%, respectively, are originating from Eawag-BBD and KEGG only. Implementation and availabilityenviLink is encoded in RDF triples as part of the enviPath RDF database. enviPath is hosted on a public webserver (envipath.org) and all data is freely available for non-commercial use. enviLink can be searched online for individual transformation rules of interest (https://tinyurl.com/y63ath3k) and is also fully downloadable from the supporting materials (i.e., Jupyter notebook "enviLink" and tsv files provided through GitHub at https://github.com/emanuel-schmid/enviLink).

bioinformatics↗

bioRxiv2018

Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets

Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering antibody-dependent phagocytosis than others. Here we quantitatively define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Increasing antigen height allows for co-localization of Fc receptors and the inhibitory phosphatase CD45 at the cell-cell interface, which reduces Fc receptor phosphorylation, and inhibits phagocytosis. Our work shows that close contact between macrophage and target cell is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.

cell biology↗