PDF(Pubmed)
Abstract：
Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness. The treatment of SEPN1 knockout mice with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) mirrors the results of ERO1A loss. Importantly, muscle biopsies from patients with SEPN1-RM exhibit ERO1A overexpression, and TUDCA-treated SEPN1-RM patient-derived primary myoblasts show improvement in bioenergetics. These findings point to ERO1A as a biomarker and a viable target for intervention and to TUDCA as a pharmacological treatment for SEPN1-RM.
摘要：
硒蛋白N（SEPN1）是内质网（ER）的一种蛋白质，其遗传性缺陷源于SEPN1相关肌病（SEPN1-RM）。这里,我们确定了SEPN1与ER应激诱导的氧化还原酶ERO1A之间的相互作用。SEPN1和ERO1A，两者都富含线粒体相关膜(MAMs)，参与蛋白质的氧化还原调节。SEPN1敲除细胞中的ERO1A耗竭可恢复ER氧化还原，重新平衡短程MAM，拯救线粒体生物能学。在SEPN1丢失的小鼠背景中的ERO1A敲除减弱了ER压力并改善了多种MAM功能，包括Ca2+水平和生物能学，从而逆转膈肌无力。用ER应激抑制剂牛磺熊去氧胆酸（TUDCA）治疗SEPN1敲除小鼠反映了ERO1A丢失的结果。重要的是,SEPN1-RM患者的肌肉活检显示ERO1A过表达，和TUDCA治疗的SEPN1-RM患者来源的原代成肌细胞在生物能学方面显示出改善。这些发现指出ERO1A作为生物标志物和干预的可行靶标，TUDCA作为SEPN1-RM的药物治疗。
