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.

中文翻译：

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PSMC3 蛋白酶体亚基变异与神经发育迟缓和 I 型干扰素产生相关

保持蛋白质稳态的一个关键步骤是被称为 PSMC1-6 的 6 个 AAA-ATPase 蛋白酶体亚基（与各种细胞活动相关的 ATPase）对蛋白质底物的识别、结合、展开和易位，这是蛋白质降解 26 所必需的。S蛋白酶体。在这里，我们鉴定了 15 个从头错义变体PSMC3编码 AAA-ATPase 蛋白酶体亚基 PSMC3/Rpt5 的基因在 23 名不相关的杂合子患者中进行，这些患者患有常染色体显性遗传性神经发育迟缓和智力障碍。表达PSMC3小鼠神经元培养物中的变异导致树突发育的改变以及树突的缺失PSMC3果蝇直系同源物 Rpt5 损害了果蝇的逆转学习能力。对源自患有以下疾病的患者的 T 细胞进行结构建模以及蛋白质组学和转录组学分析PSMC3变体涉及PSMC3通过破坏底物易位、诱导蛋白毒性应激以及控制发育和先天免疫程序的蛋白质改变，蛋白酶体功能障碍发生变异。患有以下疾病的患者的 T 细胞中的蛋白质抑制扰动PSMC3这些变异与这些 T 细胞中 I 型干扰素 (IFN) 信号传导失调相关，而这种失调可以通过抑制细胞内应激传感器蛋白激酶 R (PKR) 来阻断。这些结果表明，蛋白毒性应激激活了患者来源的 T 细胞中的 PKR，导致 I 型 IFN 反应。蛋白酶体功能障碍、I 型干扰素产生和神经发育之间的潜在关系为我们理解某些神经发育障碍的发病机制提供了新的方向。