Biology subjects

Veelen, P. v.

Publications and source records attributed to Veelen, P. v..

2 recordsLinked to original sources

bioRxiv2025

Multi-omics reveals global signaling rewiring and identifies Activin A-induced dysregulation of FOS/Activator Protein 1 as a novel target in Fibrodysplasia ossificans progressiva

BackgroundFibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation (p.R206H) in the type I BMP receptor ALK2, leading to heterotopic ossification (HO) in soft connective tissues. While aberrant Activin A-induced SMAD signaling is central in FOP pathogenesis, global signaling alterations remain poorly understood. MethodsWe performed phosphoproteomics, transcriptomics and biochemical analyses in mesenchymal cells (MSCs) overexpressing wild-type ALK2WT or mutant ALK2R206H receptors and in induced-MSCs derived from FOP patient iPSCs. Findings were validated in vivo using FOP-like mouse models and in vitro via pharmacological interventions. ResultsMulti-omics analyses revealed previously unrecognized signaling networks in ALK2R206H cells, including enhanced MAPK, mTOR, RUNX2 and RHO-mediated mechanotransduction pathways. Notably, we identified dysregulated Activator Protein-1 (AP-1) expression and function as a novel contributor to FOP. AP-1 factors were highly enriched in HO lesions in FOP-like animals. Pharmacological inhibition of AP-1 significantly reduced osteochondrogenic differentiation in vitro. ConclusionThis study highlights global signaling dysregulation in FOP and identifies AP-1 as a critical driver and potential therapeutic target for FOP.

molecular biology↗

bioRxiv2020

ERAP2 facilitates a subpeptidome of Birdshot Uveitis-associated HLA-A29

Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labelled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.

immunology↗