UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.
UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.
复制标题
DOI：
10.7554/elife.79452
复制
发表时间：
2023-03-23
期刊：
影响因子：
7.7
通讯作者：
Whiteley AM
中科院分区：
文献类型：
--
作者：
Black HH;Hanson JL;Roberts JE;Leslie SN;Campodonico W;Ebmeier CC;Holling GA;Tay JW;Matthews AM;Ung E;Lau CI;Whiteley AM
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是进行性运动神经元功能障碍和丧失。部分ALS病例是由蛋白酶体穿梭因子泛素2（UBQLN2）突变引起，但UBQLN2功能障碍导致疾病的分子途径仍不清楚。在这里，我们证明 UBQLN2 调节人类细胞和组织中驯化的 gag-pol 逆转录转座子“父系表达基因 10 (PEG10)”。在细胞中，PEG10 gag-pol 蛋白以一种类似于逆转录转座子自我加工的机制进行自身切割，生成释放的“核衣壳”片段，该片段独特地定位于细胞核并改变参与轴突重塑的基因的表达。与健康对照相比，ALS 患者的脊髓组织中 PEG10 gag-pol 升高。这些发现表明 PEG10 的逆转录转座子样活性通过基因表达的调节作为 ALS 的一种贡献机制，并且 PEG10 的抑制是 UBQLN2 的主要功能。
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon ‘paternally expressed gene 10 (PEG10)’ in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.