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

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 26S 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.

SUBMITTER: Ebstein F

PROVIDER: S-EPMC10506367 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Ebstein Frédéric F Küry Sébastien S Most Victoria V Rosenfelt Cory C Scott-Boyer Marie-Pier MP van Woerden Geeske M GM Besnard Thomas T Papendorf Jonas Johannes JJ Studencka-Turski Maja M Wang Tianyun T Hsieh Tzung-Chien TC Golnik Richard R Baldridge Dustin D Forster Cara C de Konink Charlotte C Teurlings Selina M W SMW Vignard Virginie V van Jaarsveld Richard H RH Ades Lesley L Cogné Benjamin B Mignot Cyril C Deb Wallid W Jongmans Marjolijn C J MCJ Cole F Sessions FS van den Boogaard Marie-José H MH Wambach Jennifer A JA Wegner Daniel J DJ Yang Sandra S Hannig Vickie V Brault Jennifer Ann JA Zadeh Neda N Bennetts Bruce B Keren Boris B Gélineau Anne-Claire AC Powis Zöe Z Towne Meghan M Bachman Kristine K Seeley Andrea A Beck Anita E AE Morrison Jennifer J Westman Rachel R Averill Kelly K Brunet Theresa T Haasters Judith J Carter Melissa T MT Osmond Matthew M Wheeler Patricia G PG Forzano Francesca F Mohammed Shehla S Trakadis Yannis Y Accogli Andrea A Harrison Rachel R Guo Yiran Y Hakonarson Hakon H Rondeau Sophie S Baujat Geneviève G Barcia Giulia G Feichtinger René Günther RG Mayr Johannes Adalbert JA Preisel Martin M Laumonnier Frédéric F Kallinich Tilmann T Knaus Alexej A Isidor Bertrand B Krawitz Peter P Völker Uwe U Hammer Elke E Droit Arnaud A Eichler Evan E EE Elgersma Ype Y Hildebrand Peter W PW Bolduc François F Krüger Elke E Bézieau Stéphane S

Science translational medicine 20230531 698

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<i>S</i> proteasomes. Here, we identified 15 de novo missense variants in the <i>PSMC3</i> gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal domin ...[more]

PMID: 37256937

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Project description:Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and the viral X protein (HBx) is an etiological factor in HCC development. HBx is a high-turnover protein, but knowledge of the role of deubiquitinating enzymes (DUBs) in maintaining HBx homeostasis is very limited. We used a 74-DUB library-based yeast two-hybrid assay and determined that a novel DUB, valosin-containing protein-interacting protein 1 (VCPIP1), interacted with HBx. VCPIP1 and its C-terminal amino acids 863 to 1221 upregulated the HBx protein expression, with or without HBV infection. Mechanistically, VCPIP1 stabilized HBx protein through a ubiquitin-independent pathway, which was validated by the HBx ubiquitination site mutant plasmid. Coimmunoprecipitation assays demonstrated the potency of VCPIP1 in recruiting 26S proteasome regulatory subunit 6A (PSMC3) and forming a ternary complex with HBx through mutual interaction. In vitro, purified His-tagged PSMC3 protein rescued HBx degradation induced by the 20S proteasome, and in vivo VCPIP1 synergized the mechanism. Functionally, HBx specifically binding to VCPIP1 significantly enhanced the transcriptional transactivation of HBx by activating NF-κB, AP-1, and SP-1 and inhibited hepatoma cell clonogenicity in Huh7 and HepG2 cells. Moreover, we further demonstrated that overexpression of VCPIP1 significantly affected the HBV covalently closed circular DNA (cccDNA) transcription in HBV-infected HepG2-NTCP cells. Altogether, our results indicate a novel mechanism by which VCPIP1 recruits PSMC3 to bind with HBx, stabilizing it in a ubiquitin-independent manner, which might be critical for developing DUB inhibitors in the future. IMPORTANCE HBx is a multifunctional viral oncoprotein that plays an essential role in the viral life cycle and hepatocarcinogenesis. HBx degradation occurs through the ubiquitin-proteasome system (UPS). However, whether novel compartments of the DUBs in the UPS also act in regulating HBx stability is not fully understood. Here, for the first time, we defined VCPIP1 as a novel DUB for preventing HBx degradation by the 20S proteasome in a ubiquitin-independent manner. PSMC3, encoding the 26S proteasome regulatory subunit, directly stabilized HBx through physical binding instead of a common approach in protein degradation, serving as the key downstream effector of VCPIP1 on HBx. Therefore, the ternary binding pattern between VCPIP1, HBx, and PSMC3 is initiated for the first time, which eventually promotes HBx stability and its functions. Our findings provide novel insights into host-virus cross talk by targeting DUBs in the UPS.

Dataset Information

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

Publications

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

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