Dissemin is shutting down on January 1st, 2025

Published in

American Association for the Advancement of Science, Science Translational Medicine, 698(15), 2023

DOI: 10.1126/scitranslmed.abo3189

Links

Tools

Export citation

Search in Google Scholar

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Journal article published in 2023 by Frédéric Ebstein ORCID, Sébastien Küry ORCID, Victoria Most ORCID, Cory Rosenfelt ORCID, Marie-Pier Scott-Boyer, Geeske M. van Woerden ORCID, Thomas Besnard ORCID, Jonas Johannes Papendorf, Maja Studencka-Turski ORCID, Tianyun Wang ORCID, Tzung-Chien Hsieh ORCID, Richard Golnik ORCID, Dustin Baldridge ORCID, Cara Forster, Charlotte de Konink ORCID and other authors.
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

Full text: Unavailable

Green circle
Preprint: archiving allowed
Green circle
Postprint: archiving allowed
Red circle
Published version: archiving forbidden
Data provided by SHERPA/RoMEO

Abstract

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.