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

Wolfgramm, S.; Alehashemi, S.; Wendlandt, M.; Thiel, F.G.; Jesus, A.A. de; Papendorf, J.J.; Wolfgramm, H.; Alvarez, F.L.; Borngra, E.; Uss, K.; Bhuyan, F.; Metpally, A.; Steil, L.; Hentschker, C.; Venz, S.; Abdulla, R. al; Poirier, L.; Friend, C.; Casta, F.C.; Horkayne-Szakaly, I.; Akoghlanian, S.; Mustillo, P.J.; Abraham, R.S.; Bastard, P.; Moura, T.C.L.; Dorna, M.B.; Kozu, K.T.; Kers, J.; Teng, Y.K.O.; Bredius, R.G.M.; Palmblad, K.; Horne, A.; Brodin, P.; Blanco-Lobo, P.; Bernabeu-Wittel, J.; Fernandez-Silveira, L.; Neth, O.; Pagnier, A.; Boursier, G.; Tusseau, M.; Huizinga, T.W.J.; Fournier, B.; Neven, D.; Vo, U.; Santen, G.W.E.; Brenchley, J.M.; Calvo, K.R.; Kleiner, D.; Ebstein, F.; Kru, E.; Goldbach-Mansky, R.

doi:doi:10.1016/j.ard.2025.10.021

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 /35i 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...Show moreObjectives: 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 /35i 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-a//3 receptor blockade (anifrolumab). Mechanistically, the PSMB8 p.G209R variant caused steric hindrance that impaired /35i 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.Show less

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