PXD065344

PXD065344 is an original dataset announced via ProteomeXchange.

Title	Deficiency of THSD7A reverses glomerular proteomic profiles in anti-THSD7A antibody induced membranous nephropathy models
Description	Proteomics experiment 3/3 associated with this work. THSD7A is a key podocyte antigen in membranous nephropathy (MN), an antibody-mediated autoimmune disease. While the pathogenic role of autoantibodies targeting THSD7A in MN is well described, the consequences of autoantibody binding for podocyte homeostasis as well as the functional role of THSD7A in podocytes are incompletely understood. A model of THSD7A-associated MN was induced using rabbit anti-THSD7A antibodies in wild-type (WT) as well as mice lacking THSD7A expression specifically in podocytes (Thsd7a-/- mice). Clinical and histological parameters as well as alterations in the transcriptome and proteome were analyzed. The THSD7A protein interactome was analyzed by pulldown experiments followed by proteomic identification of interaction partners. In the experimental mouse model of THSD7A-associated MN, we observed substantial protein downregulation of key slit diaphragm (SD) proteins such as nephrin and neph1, which was not a consequence of reduced SD protein transcription. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including increased interactions between extracellular matrix and receptors, and disruptions in podocyte adhesion, actin-binding, and cytoskeleton-related genes and proteins. These disruptions were at least in part driven by transcription factors such as Egr1, Egr3, Maff, Fosb and Klf4, which are involved in stress responses and inflammation. We also observed upregulation of the ubiquitin-proteasome system, lysosomal pathways, and proteases such as cathepsin S and Q, ADAM10, ADAM15 and ADAM17, which, in combination, may contribute to the loss of SD proteins in MN. While Thsd7a-/- mice only had a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Interactomic analysis of THSD7A revealed interactions with integrin 3 (ITGA3) and other glomerular proteins, implicating THSD7A complexes in pathogenic regulation of cytoskeleton organization, adhesion dynamics, and membrane signaling in MN. Anti-THSD7A antibodies induce transcriptional reprogramming and marked protein reconfiguration, including an upregulation of the proteasome and cleavage, revealing potential new therapeutic targets in MN.
HostingRepository	PRIDE
AnnounceDate	2026-01-30
AnnouncementXML	Submission_2026-01-30_10:23:44.157.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Moritz Lassé
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-23 09:00:26	ID requested
⏵ 1	2026-01-30 10:23:44	announced

Dataset with its publication pending

submitter keyword: anti-THSD7A antibody induced membranous nephropathy, podocyte injury, experimental membranous nephropathy

Markus M. Rinschen
contact affiliation	Aarhus University Department of Biomedicine DK-8000 Aarhus
contact email	rinschen@biomed.au.dk
lab head
Moritz Lassé
contact affiliation	Zentrum für Innere Medizin, III. Medizinische Klinik und Poliklinik (Nephrologie/Rheumatologie/Endokrinologie), Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany
contact email	moritz.lasse@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065344
     1. Label: PRIDE project
     2. Name: Deficiency of THSD7A reverses glomerular proteomic profiles in anti-THSD7A antibody induced membranous nephropathy models