Senescence of nondividing neurons remains an immature concept, with especially the regulatory molecular mechanisms of senescence-like phenotypes and the role of proteins associated with neurodegenerative diseases in triggering neuronal senescence remaining poorly explored. In this study, we reveal that the nucleolar polyglutamine binding protein 3 (PQBP3; also termed NOL7), which has been linked to polyQ neurodegenerative diseases, regulates senescence as a gatekeeper of cytoplasmic DNA leakage. PQBP3 directly binds PSME3 (proteasome activator complex subunit 3), a subunit of the 11S proteasome regulator complex, decreasing PSME3 interaction with Lamin B1 and thereby preventing Lamin B1 degradation and senescence. Depletion of endogenous PQBP3 causes nuclear membrane instability and release of genomic DNA from the nucleus to the cytosol. Among multiple tested polyQ proteins, ataxin-1 (ATXN1) partially sequesters PQBP3 to inclusion bodies, reducing nucleolar PQBP3 levels. Consistently, knock-in mice expressing mutant Atxn1 exhibit decreased nuclear PQBP3 and a senescence phenotype in Purkinje cells of the cerebellum. Collectively, these results suggest homologous roles of the nucleolar protein PQBP3 in cellular senescence and neurodegeneration.

中文翻译：

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PQBP3 通过抑制 PSME3 介导的蛋白酶体 Lamin B1 降解来预防衰老。


非分裂神经元的衰老仍然是一个不成熟的概念，特别是衰老样表型的调节分子机制以及与神经退行性疾病相关的蛋白质在触发神经元衰老中的作用仍然缺乏探索。在这项研究中，我们揭示了核仁聚谷氨酰胺结合蛋白 3（PQBP3；也称为 NOL7）与 PolyQ 神经退行性疾病有关，它作为细胞质 DNA 泄漏的看门人来调节衰老。 PQBP3 直接结合 PSME3（蛋白酶体激活复合物亚基 3）（11S 蛋白酶体调节复合物的亚基），减少 PSME3 与核纤层蛋白 B1 的相互作用，从而防止核纤层蛋白 B1 降解和衰老。内源性 PQBP3 的消耗会导致核膜不稳定以及基因组 DNA 从细胞核释放到细胞质。在多种测试的 PolyQ 蛋白中，ataxin-1 (ATXN1) 将 PQBP3 部分隔离于包涵体，从而降低核仁 PQBP3 水平。一致地，表达突变体 Atxn1 的敲入小鼠表现出核 PQBP3 减少和小脑浦肯野细胞的衰老表型。总的来说，这些结果表明核仁蛋白 PQBP3 在细胞衰老和神经变性中具有同源作用。