Monoallelic PSMB8 variants cause immunodeficiency and autoinflammation through impaired immunoproteasome assembly

Machteld M. Oud1,31 Send email to [email protected]

15d ago· 39 min readenInsight

Summary

This study identifies seven individuals from five unrelated families carrying five distinct monoallelic PSMB8 variants that cause proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement, along with inflammatory manifestations. The research demonstrates that mutant PSMB8 proteins are inefficiently incorporated into immunoproteasome complexes, impairing assembly and triggering cellular stress responses through a dominant-negative mechanism that unifies PRAAS-IDs and highlights structural vulnerabilities in catalytic subunits.

Source

bskyMonoallelic PSMB8 variants cause immunodeficiency and autoinflammation through impaired immunoproteasome assemblycell.com

Key quotes

· 4 pulled

Seven individuals from five unrelated families carrying five distinct monoallelic PSMB8 variants were identified.

Individuals presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement.

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.

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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 ce

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