Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly

Seven individuals from five families harboring monoallelic PSMB8 variants presented with immunodeficiency and systemic inflammation. Mutant PSMB8 proteins are inefficiently incorporated into immunoproteasome complexes, impairing assembly and triggering cellular stress responses. This dominant-negative mechanism unifies PRAAS-IDs and highlights structural vulnerabilities in catalytic subunits.