Biology subjects

Braubach, P.

Publications and source records attributed to Braubach, P..

5 recordsLinked to original sources

bioRxiv2026

Cell-specific FUS loss enhances ageing-associated transcriptional elongation in lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-related, lethal lung disease affecting over 3 million people worldwide. During aging, impairment of diverse molecular processes compromises cellular homeostasis. Eukaryotic cells adapt to this ageing-associated stress by large-scale transcriptome changes affecting the expression of genes involved in signaling, protein homeostasis, cell plasticity and immune response. The molecular mechanisms regulating extensive transcriptome rearrangements leading to senescence in specific cell types of IPF lungs remain sparsely investigated. Here we uncover fundamental molecular mechanisms underlying cellular senescence by integrative analysis of multi-omics studies and functional experiments monitoring fibrotic and senescence hallmarks in primary lung fibroblasts from control and IPF patients. Loss-of-function of the DNA/RNA binding protein fused in sarcoma (FUS) in control fibroblasts enhanced fibrotic and senescence hallmarks resembling IPF fibroblasts. Dissecting the molecular mechanisms, reduced FUS levels in IPF fibroblasts abolished R-loop formation at transcription start sites (TSS), leading to increased RNA polymerase II (Pol II) recruitment and its phosphorylation at serine 2, resulting in enhanced translocation speed of elongating Pol II and increased expression of fibrosis- and senescence-related genes. Summarizing, FUS maintains low Pol II processivity in control fibroblasts by stabilizing R-loops at TSS, acting as a gatekeeper of fibrotic and age-associated transcriptional programs.

molecular biology↗

bioRxiv2025

The pleuroparenchymal fibroelastosis atlas reveals aberrant cell states and their zonation as an alternate roadmap to lung fibrosis

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease with higher prevalence in females, histologically characterized by intra-alveolar fibrosis with septal elastosis (AFE). Effective treatments are lacking, highlighting the need to dissect its pathogenesis at single-cell resolution. MethodsWe performed single-nucleus RNA sequencing (snRNAseq) on explanted lungs from a German (n=23) and a French cohort (n=17) of PPFE patients, and controls (n=16). Identified cell populations were localized by immunofluorescence and multiplex RNA in-situ hybridization. Hierarchical phase-contrast computed tomography (HiP-CT) and micro-CT provided 3D spatial context. Reanalyzed snRNAseq data from a Belgian IPF cohort (n=9) served as disease comparator. FindingsWe present the first snRNAseq atlas of PPFEs cellular and structural landscape based on a European multinational cohort. 24 PPFE patients were female (60.0%), while 34 were non-smokers (85.0%). 519,920 nuclear transcriptomes from PPFE and IPF patients, and controls were profiled. We identified PPFE-specific accumulations of MFAP5+PI16+SFRP2+ adventitial and LEPR+ITGA8+SFRP2+DIO2+ elastofibrotic fibroblasts as main drivers of elastotic remodeling in PPFE. Multiple PPFE fibroblast subsets acquire an inflammatory activation state as highlighted by the expression of CXCL12 and CXCL14. This is accompanied by a marked increase in lymphocytes and the formation of tertiary lymphoid structures (TLS) in a disease that was previously considered to be purely elastofibrotic. We identified CTHRC1+ fibrotic fibroblasts and Aberrant Basaloid cells in PPFE as well, forming the "Usual Fibrotic Niche". 3D reconstruction of the pronounced COL15A1+ vascular conglomerate at the border of the elastofibrotic and subpleural fibrosis indicates communication with interlobar veins. Last, we observed a zonation of the PPFE lesion, constructed by the above-mentioned PPFE-associated cell types. InterpretationOur unprecedented cellular and molecular survey uncovers previously unobserved PPFE-specific inflammatory and elastogenic fibroblast populations, as well as the presence of CTHRC1+ fibroblasts and Aberrant Basaloid cells common to other fibrotic ILDs. These findings provide the foundation for including PPFE patients in current antifibrotic trials, as well as development of PPFE-specific therapies. FundingSupported mainly by the Else Kroner-Fresenius Foundation, the German Center for Lung Research and the Fondation du Souffle.

cell biology↗

bioRxiv2025

Trypstatin as a Novel TMPRSS2 Inhibitor with Broad-Spectrum 1 Efficacy Against Corona and Influenza Viruses

Respiratory viruses, such as SARS-CoV-2 and influenza, exploit host proteases like TMPRSS2 for entry, making TMPRSS2 a prime antiviral target. Here, we report the identification and characterization of Trypstatin, a 61-amino acid Kunitz-type protease inhibitor derived from human hemofiltrate. Trypstatin inhibits TMPRSS2 and related proteases, with IC50 values in the nanomolar range, comparable to the small molecule inhibitor camostat mesylate. In vitro assays demonstrated that Trypstatin effectively blocks spike-driven entry of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and hCoV-NL63, as well as hemagglutinin-mediated entry of influenza A and B viruses. In primary human airway epithelial cultures, Trypstatin significantly reduced SARS-CoV-2 replication and retained activity in the presence of airway mucus. In vivo, intranasal administration of Trypstatin to SARS-CoV-2-infected Syrian hamsters reduced viral titers and alleviated clinical symptoms. These findings highlight Trypstatins potential as a broad-spectrum antiviral agent against TMPRSS2-dependent respiratory viruses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/632953v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1b90566org.highwire.dtl.DTLVardef@117293org.highwire.dtl.DTLVardef@1794959org.highwire.dtl.DTLVardef@1be9090_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Extracellular vesicles induce aggressive lung cancervia non-canonical integrin-EGFR-KRAS signaling

Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC has remained elusive. We analyzed RNA-sequencing data, human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines to demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which might be used for stratification of SCLC patients, prognosis prediction of LC patients and development of patient-tailored therapies. We also found by proteomic analysis a cell-cell communication mechanism based on extracellular vesicles (EVs) containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers. We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type.

cancer biology↗

bioRxiv2022

The Idiopathic Pulmonary Fibrosis-associated single nucleotide polymorphism rs35705950 is transcribed in a MUC5B PromoterAssociated Long Non-Coding RNA(AC061979.1)

LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps the recently annotated lncRNA AC061979.1, a 1,712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry.

cell biology↗