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Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis
eLife ( IF 6.4 ) Pub Date : 2020-07-10 , DOI: 10.7554/elife.56584
Lingna Xu 1 , Xi Wang 1 , Jia Zhou 1 , Yunyi Qiu 1 , Weina Shang 1 , Jun-Ping Liu 2 , Liquan Wang 3 , Chao Tong 1, 2, 3
Affiliation  

Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, and mitochondrial dynamics. However, the molecular organization, functions, regulation of ERMCS, and the physiological roles of altered ERMCSs are not fully understood in higher eukaryotes. We found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga-mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.

中文翻译:

Miga 介导的内质网-线粒体接触位点调节神经元稳态

内质网 (ER)-线粒体接触位点 (ERMCS) 对钙信号、脂质转运和线粒体动力学等多种细胞过程至关重要。然而,在高等真核生物中,ERMCS 的分子组织、功能、调节以及改变的 ERMCS 的生理作用尚未完全了解。我们发现,线粒体定位蛋白 Miga 显着增加了 ERMCS,并在果蝇眼中过度表达时导致严重的神经变性。Miga 通过其 FFAT 样基序与 ER 蛋白 Vap33 相互作用,肌萎缩侧索硬化 (ALS) 疾病相关的 Vap33 突变大大降低了其与 Miga 的相互作用。Miga FFAT 基序内部和附近的多个丝氨酸残基被磷酸化,这是其与 Vap33 和 Miga 介导的 ERMCS 形成相互作用所必需的。Vap33 和 Miga 之间的相互作用促进了上游丝氨酸/苏氨酸簇的进一步磷酸化,从而微调了 Miga 的活性。蛋白激酶 CKI 和 CaMKII 有助于 Miga 过度磷酸化。MIGA2 由 miga 哺乳动物直向同源基因编码,在哺乳动物细胞中具有保守的功能。我们提出了一个模型,该模型显示 Miga 与 Vap33 相互作用以介导 ERMCS,而过多的 ERMCS 会导致神经变性。
更新日期:2020-07-10
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