Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia
Year: 2026
Type: article
Study design: Case Report
Abstract: Immunoproteasomes are specialized multiprotein proteases that degrade intracellular proteins. Their products serve as peptides for human leukocyte antigen class I presentation playing a key role in antiviral defense and self-tolerance. Monoallelic variants in immunoproteasome genes including proteasome subunit β type 10 have recently been associated with autoinflammatory diseases and severe combined immune deficiency. Their pathophysiological consequences remain poorly understood, and treatment options are scarce. We identified a newborn with severe T lymphopenia and a de novo dominant-negative PSMB10 p.G209R mutation after pathological T cell receptor excision circle newborn screening. We further applied molecular modeling, proteomics, transcriptomics, and ex vivo T lymphopoiesis. Simulations predicted, and biochemical studies confirmed, impaired immunoproteasome assembly and function leading to defective viral sensing and antigen presentation signatures in interferon-treated fibroblasts. Despite this, hematopoietic stem cells differentiated into T cells ex vivo, and the patient developed normal naïve T cell counts and a diverse T cell antigen receptor repertoire within the first year of life in contrast to all previously reported patients.
Source: Journal of Human Immunity
Authors: Sujal Ghosh, Yuqin Wang, Christoph Schultheiss, Arndt Borkhardt, Angelique Sanchez Dafun, Liisa Knipp, Sebastian Marwitz, Stephan Ehl, Clara Soulard, Elie Haddad, Debayan Dey, Grace Evans, Zainab M. Golwala, Sabrina B. Bennstein, Hans-Jürgen Laws, Meino Rohlfs, Thomas Magg, Mascha Binder, Alexandra Y. Kreins, Marie-Pierre Bousquet, Julien Marcoux, Christoph Klein, Graeme L. Conn, Silke Meiners, Fabian Hauck
Institutions: Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Research Center Borstel - Leibniz Lung Center, German Center for Lung Research, University Hospital of Basel, Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, University of Freiburg, University Medical Center Freiburg, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Emory University, University College London, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, RWTH Aachen University, LMU Klinikum, Ludwig-Maximilians-Universität München, Christian-Albrechts-Universität zu Kiel
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
Awards: G1747846221, Improving the outcome of children with congenital athymia., G3920001115, Improving the outcome of children with congenital athymia., GAIN - Deutsches Netzwerk für die Erforschung und Therapieoptimierung von Patienten mit genetischen Multi-Organ-Autoimmunerkrankungen: Analyse der Pathomechanismen und Multi-Organ-Autoimmunität der monoallelischen CARD11 Keimbahnvarianten und Testung einer zielgerichteten pharmakologischen Intervention
OpenAlex ID: W7153112244