Department of Biochemistry, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.
Mol Cell. 2018 Jun 7;70(5):906-919.e7. doi: 10.1016/j.molcel.2018.04.021. Epub 2018 May 24.
Stress granules (SGs) are cytoplasmic assemblies of mRNPs stalled in translation initiation. They are induced by various stress conditions, including exposure to the environmental toxin and carcinogen arsenic. While perturbed SG turnover is linked to the pathogenesis of neurodegenerative diseases, the molecular mechanisms underlying SG formation and turnover are still poorly understood. Here, we show that ZFAND1 is an evolutionarily conserved regulator of SG clearance. ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. In the absence of ZFAND1, SGs lack the 26S proteasome and p97, accumulate defective ribosomal products, and persist after arsenite removal, indicating their transformation into aberrant, disease-linked SGs. Accordingly, ZFAND1 depletion is epistatic to the expression of pathogenic mutant p97 with respect to SG clearance, suggesting that ZFAND1 function is relevant to the multisystem degenerative disorder IBMPFD/ALS.
应激颗粒（SGs）是翻译起始阶段停滞的 mRNP 的细胞质聚集体。它们是由各种应激条件诱导的，包括暴露于环境毒素和致癌剂砷。虽然扰动 SG 周转率与神经退行性疾病的发病机制有关，但 SG 形成和周转率的分子机制仍知之甚少。在这里，我们表明 ZFAND1 是 SG 清除的进化保守调节剂。ZFAND1 与两种关键的蛋白降解因子，即 26S 蛋白酶体和泛素选择性分离酶 p97 相互作用，并将它们募集到亚砷酸盐诱导的 SG 中。在没有 ZFAND1 的情况下，SG 缺乏 26S 蛋白酶体和 p97，积累有缺陷的核糖体产物，并在去除亚砷酸盐后仍然存在，表明它们转化为异常的、与疾病相关的 SG。因此，ZFAND1 缺失对于 SG 清除来说是致病性突变体 p97 表达的上位性，这表明 ZFAND1 功能与多系统退行性疾病 IBMPFD/ALS 有关。
