257: PSMC5: proteasomes, immunity and neurodevelopment

Küry S et al., Nature Communications, doi:10.1038/s41467-025-65556-8 - This study describes 26 distinct PSMC5 variants in 44 individuals and demonstrates that PSMC5 loss impairs proteasome function, driving proteotoxic stress, mitochondrial and lipid dysregulation, sterile type I interferon activation, and neurodevelopmental deficits. Key terms: PSMC5, proteasome, neurodevelopment, interferon, mitophagy. Study Highlights:Twenty-six distinct PSMC5 variants were identified in 44 affected individuals, mostly heterozygous and de novo, clustering in the AAA+ ATPase domain and predicted to be pathogenic. Functional assays and patient T cells show that many variants perturb PSMC5 incorporation into 26S proteasomes, reduce proteasome activity, and increase ubiquitin-positive aggregates and aggresomes. Multi-omics of patient T cells revealed disrupted mitochondrial proteostasis with increased mitophagy, altered glycerophospholipid profiles and impaired ribosome biogenesis. Neuronal models and Drosophila demonstrate reduced excitatory synapses, E/I imbalance, impaired neuritogenesis, deficits in reversal learning and compromised NPC differentiation, while ISR kinases PKR and GCN2 plus cGAS-STING and JAK pathways mediate a spontaneous type I IFN response that can be pharmacologically reduced. Conclusion:PSMC5 variants cause proteasome loss-of-function that links proteotoxic stress to innate immune activation and impaired neurogenesis, identifying ISR and JAK pathway components as potential therapeutic targets. Music:Enjoy the music based on this article at the end of the episode. Article title:Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies First author:Küry S Journal:Nature Communications, doi:10.1038/s41467-025-65556-8 DOI:10.1038/s41467-025-65556-8 Reference:Küry S, Bézieau S, Ebstein F, et al. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nature Communications. 2025;16:10545. https://doi.org/10.1038/s41467-025-65556-8 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/psmc5-proteasome-neurodevelopment QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the spoken content describing PSMC5/UPS biology, variant effects, multi-model analyses (Drosophila, rat neurons, iPSC-derived NPCs), ISR and IFN signaling, lipid/mitophagy changes, synaptic balance, and therapeutic implications.- transcript topics: PSMC5 and 26S proteasome function; PSMC5 variants and neurodevelopmental proteasomopathies; Proteotoxic stress and aggresome formation; Mitochondrial dysfunction and mitophagy; Lipid metabolism dysregulation; Integrated stress response (PKR/GCN2) and type I interferon signaling QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- 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:- 26 distinct PSMC5...