TY - JOUR
T1 - A de novo dominant-negative PSMB8 mutation causes severe CANDLE/PRAAS due to arrested proteasome biogenesis
AU - Wolfgramm, Sophie
AU - Alehashemi, Sara
AU - Wendlandt, Martin
AU - Thiel, Franziska G.
AU - de Jesus, Adriana A.
AU - Papendorf, Jonas J.
AU - Wolfgramm, Hannes
AU - Alvarez, Flavia Llorente
AU - Borngräber, Emely
AU - Uss, Kat
AU - Bhuyan, Farzana
AU - Metpally, Anvitha
AU - Steil, Leif
AU - Hentschker, Christian
AU - Venz, Simone
AU - Abdulla, Ruba Al
AU - Poirier, L.
AU - Friend, Christopher
AU - Casta, Fabiola Castello
AU - Horkayne-Szakaly, Iren
AU - Akoghlanian, Shoghik
AU - Mustillo, Peter J.
AU - Abraham, Roshini S.
AU - Bastard, Paul
AU - Moura, Thais C. L.
AU - Dorna, Mayra B.
AU - Kozu, Katia T.
AU - Kers, Jesper
AU - Teng, Y. K. Onno
AU - Bredius, Robbert G. M.
AU - Palmblad, Karin
AU - Horne, AnnaCarin
AU - Brodin, Petter
AU - Blanco-Lobo, Pilar
AU - Bernabeu-Wittel, José
AU - Fernandez-Silveira, Laura
AU - Neth, Olaf
AU - Pagnier, Anne
AU - Boursier, Guilaine
AU - Tusseau, Maud
AU - Huizinga, Thomas W. J.
AU - Fournier, Benjamin
AU - Neven, B. nédicte
AU - Völker, Uwe
AU - Santen, Gijs W. E.
AU - Brenchley, Jason M.
AU - Calvo, Katherine R.
AU - Kleiner, David
AU - Ebstein, Frédéric
AU - Krüger, Elke
AU - Goldbach-Mansky, Raphaela
N1 - Publisher Copyright:
© 2025 The Author(s). Published by Elsevier B.V. on behalf of European Alliance of Associations for Rheumatology (EULAR). This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
PY - 2025
Y1 - 2025
N2 - 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 kinase R (PKR) and general control nonderepressible 2 (GCN2), and by Janus kinase signalling. Conclusions: The DN-PSMB8 p.G209R variant broadens the clinical and mechanistic PRAAS spectrum by causing 20S proteasome maturation arrest and uncovering a convergence between mitochondrial dysfunction and the ISR. Our findings implicate cytopenia in a pattern of vascular pathology, including PSVD of the liver. We further identify PKR and GCN2 as key mediators of maladaptive IFN-I responses and potential therapeutic targets.
AB - 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 kinase R (PKR) and general control nonderepressible 2 (GCN2), and by Janus kinase signalling. Conclusions: The DN-PSMB8 p.G209R variant broadens the clinical and mechanistic PRAAS spectrum by causing 20S proteasome maturation arrest and uncovering a convergence between mitochondrial dysfunction and the ISR. Our findings implicate cytopenia in a pattern of vascular pathology, including PSVD of the liver. We further identify PKR and GCN2 as key mediators of maladaptive IFN-I responses and potential therapeutic targets.
UR - https://www.scopus.com/pages/publications/105023855063
U2 - 10.1016/j.ard.2025.10.021
DO - 10.1016/j.ard.2025.10.021
M3 - Article
C2 - 41253591
SN - 0003-4967
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
ER -