A de novo dominant-negative PSMB8 mutation causes severe CANDLE/PRAAS due to arrested proteasome biogenesis

作者：Sophie Wolfgramm, Sara Alehashemi, Martin Wendlandt, Franziska G. Thiel, Adriana A. de Jesus, Jonas Johannes Papendorf, Hannes Wolfgramm, Flavia Llorente Alvarez, Emely Borngräber, Kat Uss, Farzana Bhuyan, Anvitha Metpally, Leif Steil, Christian Hentschker, Simone Venz, Ruba Al‐Abdulla, Léa Poirier, Christopher Friend, Fabiola Castello Casta, Iren Horkayne‐Szakaly, Shoghik Akoghlanian, Peter Mustillo, Roshini S. Abraham, Paul Bastard, Thais Costa Lima de Moura, Mayra Dorna, Kátia Tomie Kozu, Jesper Kers, Y K Onno Teng, Robbert G. M. Bredius, Karin Palmblad, AnnaCarin Horne, Petter Brodin, Pilar Blanco-Lobo, José Bernabéu‐Wittel, Laura Fernandez-Silveira, Olaf Neth, Anne Pagnier, G. Boursier, Maud Tusseau, T. Huizinga, Benjamin Fournier, Bénédicte Neven, Uwe Völker, Gijs W.E. Santen, Jason M. Brenchley, Katherine R. Calvo, David E. Kleiner, Frédéric Ebstein, Elke Krüger, Raphaela Goldbach‐Mansky · 发表于：Annals of the Rheumatic Diseases · 年份：2025 · DOI：10.1016/j.ard.2025.10.021 · 被引用次数：6 · 研究领域：Ubiquitin and proteasome pathways、Nuclear Structure and Function、Lipid metabolism and disorders

OBJECTIVES: Proteasome-associated autoinflammatory syndromes (PRAAS) include a group of autoinflammatory interferonopathies caused by 20S proteasome dysfunction. We characterised pathomechanisms and treatment responses of patients with a de novo, dominant-negative (DN)-proteasome subunit beta type-8 (PSMB8) variant. METHODS: Patients with the DN-PSMB8 p.G209R variant encoding a mutant β5i subunit of the 20S immunoproteasome were evaluated. Interferon biomarkers, proteasome activity, structural modelling, and proteotoxic stress responses were assessed. Patients' T cells underwent integrated transcriptomic and proteomic profiling to characterise immune dysregulation, proteotoxic stress responses, mitochondrial function, and type I interferon (IFN-I) associated stress signalling. RESULTS: Patients with DN-PRAAS presented with early-onset systemic inflammation, panniculitis, cytopenias, infections, and porto-sinusoidal vascular liver disease (PSVD), indicating broader immune dysfunction that partially responds to Janus kinase inhibition and/or interferon-α/β receptor blockade (anifrolumab). Mechanistically, the PSMB8 p.G209R variant caused steric hindrance that impaired β5i propeptide processing and final 20S proteasome formation, resulting in intracellular protein aggregation, impaired mitochondrial metabolism, and altered neutral lipid processing. The IFN-I signature of patients' T cells was reduced by blockade of 2 integrated stress response (ISR)-regulating kinases, protein k...