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

蛋白酶体 生物 蛋白质亚单位 蛋白质稳态 细胞生物学 干扰素 蛋白质降解 转录组 未折叠蛋白反应 HEK 293细胞 ISG15 蛋白激酶R 野生型 激酶 遗传学 基因 蛋白激酶A 泛素 基因表达 细胞周期蛋白依赖激酶2 突变体
作者
Frédéric Ebstein,Sébastien Küry,Victoria Most,Cory Rosenfelt,Marie-Pier Scott-Boyer,Geeske M. van Woerden,Thomas Besnard,Jonas Johannes Papendorf,Maja Studencka-Turski,Tianyun Wang,Tzung-Chien Hsieh,Richard Golnik,Dustin Baldridge,Cara Forster,Charlotte de Konink,S. M. W. Teurlings,Virginie Vignard,Richard H. van Jaarsveld,Lesley C. Adès,Benjamin Cogné,Cyril Mignot,Wallid Deb,Marjolijn C.J. Jongmans,F. Sessions Cole,Marie-José H. van den Boogaard,Jennifer A. Wambach,D.J. Wegner,Sandra Yang,Vickie Hannig,Jennifer Brault,Neda Zadeh,Bruce Bennetts,Boris Keren,Anne‐Claire Gelineau,Zöe Powis,Meghan C. Towne,Kristine Bachman,Andrea Seeley,Anita E. Beck,Jennifer R. Morrison,Rachel Westman,Kelly Averill,Theresa Brunet,Judith Haasters,Melissa T. Carter,Matthew Osmond,Patricia G. Wheeler,Francesca Forzano,Shehla Mohammed,Yannis Trakadis,Andrea Accogli,Rachel Harrison,Yiran Guo,Hakon Hakonarson,Sophie Rondeau,Geneviève Baujat,Giulia Barcia,René G. Feichtinger,Johannes A. Mayr,Martin Preisel,Frédéric Laumonnier,Tilmann Kallinich,Alexej Knaus,Bertrand Isidor,Peter Krawitz,Uwe Völker,Elke Hammer,Arnaud Droit,Evan E. Eichler,Ype Elgersma,Peter W. Hildebrand,François Bolduc,Elke Krüger,Stéphane Bézieau
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:15 (698) 被引量:3
标识
DOI:10.1126/scitranslmed.abo3189
摘要

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.
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