378: Dominant-negative PSMB8 variants stall immunoproteasome assembly

Wijngaard R et al., The American Journal of Human Genetics - Researchers describe seven individuals with monoallelic PSMB8 missense variants that impair immunoproteasome assembly, causing early-onset immunodeficiency and variable systemic inflammation via a dominant-negative mechanism. Key terms: PSMB8, immunoproteasome, PRAAS-ID, immunodeficiency, proteasome assembly.

Study Highlights:
Seven individuals from five families carrying distinct monoallelic PSMB8 variants presented with neonatal-onset immunodeficiency, B cell lymphopenia, hypogammaglobulinemia, and variable inflammatory disease. Structural modeling predicted destabilization of proteasome interfaces, and complexome profiling plus native assays showed reduced fully assembled immunoproteasomes with accumulation of a ∼440-kDa assembly intermediate. Mutant PSMB8 precursors accumulated, incorporation into 20S/26S complexes was reduced, immunoproteasome-specific activity decreased, and integrated stress response genes were induced. These data support a shared dominant-negative mechanism disrupting immunoproteasome biogenesis and immune signaling.

Conclusion:
Monoallelic PSMB8 missense variants impair incorporation of β5i into assembling immunoproteasomes, stalling biogenesis, reducing immunoproteasome abundance and activity, and producing clinically variable immunodeficiency with systemic inflammation consistent with PRAAS-ID.

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Article title:
Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly

First author:
Wijngaard R

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.04.015

Reference:
Wijngaard R., van der Made C.I., Kalkan Uçar S., et al. Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly. Am J Hum Genet. 2026;113:1–19. doi:10.1016/j.ajhg.2026.04.015

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/monoallelic-psmb8-praas-id-immunoproteasome-assembly

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of immunoproteasome biology, dominant-negative mechanism of monoallelic PSMB8 variants, complexome profiling findings (440-kDa assembly intermediate, reduced IP abundance), functional consequences (IP activity reduction, ISR activation), and clinical implications described in the transcript.
- transcript topics: Immunoproteasome structure and SP/IP distinction; Dominant-negative PSMB8 variants and mechanism; Complexome profiling methodology and IP assembly intermediates; Impaired IP biogenesis and 440-kDa intermediate; ISR activation and immune signaling effects; Clinical features: B cell lymphopenia, hypogammaglobulinemia, leukocyte inclusions

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Monoallelic PSMB8 variants cause PRAAS-ID via dominant-negative impairment of immunoproteasome assembly
- Mutant PSMB8 subunits are inefficiently incorporated into immunoproteasomes, leading to defective IP biogenesis and reduced IP activity
- Complexome profiling reveals accumulation of a ~440-kDa IP assembly intermediate with assembly factors
- The 440-kDa intermediate is catalytically inactive despite partial assembly
- Leukocyte vacuolization and inclusions observed in blood/bone marrow
- B cell lymphopenia and hypogammaglobulinemia, frequently requiring IVIG

QC result: Pass.