Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia
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.
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BibTeX
@article{ghosh2026dominantnegative,
title = {{Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia}},
author = {Sujal Ghosh and Yuqin Wang and Christoph Schultheiss and Arndt Borkhardt and Angelique Sanchez Dafun and Liisa Knipp and Sebastian Marwitz and Stephan Ehl and Clara Soulard and Elie Haddad and Debayan Dey and Grace Evans and Zainab M Golwala and Sabrina B Bennstein and Hans-Jürgen Laws and Meino Rohlfs and Thomas Magg and Mascha Binder and Alexandra Y Kreins and Marie-Pierre Bousquet and Julien Marcoux and Christoph Klein and Graeme L Conn and Silke Meiners and Fabian Hauck},
journal = {Journal of Human Immunity},
year = {2026},
month = oct,
doi = {10.70962/jhi.20250129},
url = {https://hal.science/hal-05844244v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia
AU - Sujal Ghosh
AU - Yuqin Wang
AU - Christoph Schultheiss
AU - Arndt Borkhardt
AU - Angelique Sanchez Dafun
AU - Liisa Knipp
AU - Sebastian Marwitz
AU - Stephan Ehl
AU - Clara Soulard
AU - Elie Haddad
AU - Debayan Dey
AU - Grace Evans
AU - Zainab M Golwala
AU - Sabrina B Bennstein
AU - Hans-Jürgen Laws
AU - Meino Rohlfs
AU - Thomas Magg
AU - Mascha Binder
AU - Alexandra Y Kreins
AU - Marie-Pierre Bousquet
AU - Julien Marcoux
AU - Christoph Klein
AU - Graeme L Conn
AU - Silke Meiners
AU - Fabian Hauck
PY - 2026
DA - 2026/10/29
JO - Journal of Human Immunity
DO - 10.70962/jhi.20250129
UR - https://hal.science/hal-05844244v1
AB - 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.
SN - 3065-8993
SN - 3065-8993
ER -