TY - JOUR
T1 - Complexome profiling showed impaired immunoproteasome assembly in a novel PRAAS subtype caused by monoallelic PSMB8 variants
AU - Wijngaard, Robin
AU - van der Made, Caspar I
AU - Kalkan Uçar, Sema
AU - Ramakrishnan, Gayatri
AU - Rosenfeld, Jill A
AU - Vogel, Tiphanie P
AU - Nicholas, Sarah K
AU - Weisz-Hubshman, Monika
AU - Undiagnosed Diseases Network
AU - Cabrera-Orefice, Alfredo
AU - Siebels, Bente
AU - Mair, Thomas
AU - Schlüter, Hartmut
AU - Smeets, Ruben L
AU - van Beek, Ronald
AU - van Karnebeek, Clara D M
AU - Hoischen, Alexander
AU - Vissers, Lisenka E L M
AU - Wortmann, Saskia B
AU - Wevers, Ron A
AU - Oud, Machteld M
AU - Guerrero-Castillo, Sergio
N1 - PREPRINT! Wortmann: University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
PY - 2025/6/26
Y1 - 2025/6/26
N2 - Immunoproteasomes, essential for MHC class I antigen presentation, differ from standard proteasomes by incorporating the catalytic subunits PSMB9 (β1i), PSMB10 (β2i), and PSMB8 (β5i). Proteasome-associated autoinflammatory syndromes (PRAAS) are type I interferonopathies resulting from impaired proteasome function. Here, we describe two individuals carrying monoallelic de novo variants in PSMB8 , both presenting with early-onset systemic autoinflammation and features of immunodeficiency, accompanied by a marked type I interferon response. To investigate the underlying mechanism, we performed complexome profiling on interferon-γ-stimulated fibroblasts harboring the p.(Ala235Asp) variant. This variant, located at the β-ring interface, disrupted proper assembly of the immunoproteasome, resulting in reduced levels of fully assembled 20S and 26S immunoproteasomes and accumulation of assembly intermediates. The findings suggest a dominant-negative effect and broaden the clinical and genetic spectrum of PRAAS with immunodeficiency (PRAAS-ID), while highlighting the utility of complexome profiling to study proteasome assembly defects.
AB - Immunoproteasomes, essential for MHC class I antigen presentation, differ from standard proteasomes by incorporating the catalytic subunits PSMB9 (β1i), PSMB10 (β2i), and PSMB8 (β5i). Proteasome-associated autoinflammatory syndromes (PRAAS) are type I interferonopathies resulting from impaired proteasome function. Here, we describe two individuals carrying monoallelic de novo variants in PSMB8 , both presenting with early-onset systemic autoinflammation and features of immunodeficiency, accompanied by a marked type I interferon response. To investigate the underlying mechanism, we performed complexome profiling on interferon-γ-stimulated fibroblasts harboring the p.(Ala235Asp) variant. This variant, located at the β-ring interface, disrupted proper assembly of the immunoproteasome, resulting in reduced levels of fully assembled 20S and 26S immunoproteasomes and accumulation of assembly intermediates. The findings suggest a dominant-negative effect and broaden the clinical and genetic spectrum of PRAAS with immunodeficiency (PRAAS-ID), while highlighting the utility of complexome profiling to study proteasome assembly defects.
U2 - 10.1101/2025.06.25.25330124
DO - 10.1101/2025.06.25.25330124
M3 - Original Article
C2 - 40666351
JO - medRxiv : the preprint server for health sciences
JF - medRxiv : the preprint server for health sciences
ER -