Abstract
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.