Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster.
Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster.
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DOI：
10.1371/journal.pone.0151550
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Heino TI
中科院分区：
文献类型：
--
作者：
Lindström R;Lindholm P;Kallijärvi J;Palgi M;Saarma M;Heino TI
内质网（ER）稳态的紊乱被称为ER应激，与多种人类疾病有关。ER应激激活未折叠蛋白反应（UPR），这是一种细胞机制，其目的是恢复ER稳态。以往的研究表明，中脑星形胶质细胞源性神经营养因子（MANF）是一个重要的新的组成部分，在调节UPR。在脊椎动物中，MANF被ER应激上调，并保护细胞免受ER应激诱导的细胞死亡。生物化学研究揭示了哺乳动物MANF和GRP78之间的相互作用，GRP78是促进蛋白质折叠的主要ER伴侣。在这项研究中，我们发现，在药物诱导的内质网应激反应中，MANF表达的上调在果蝇和哺乳动物之间是保守的。此外，通过使用体内遗传方法，我们发现果蝇Manf和编码果蝇同源物GRP78，PERK和XBP1（UPR的关键成分）的基因之间的遗传相互作用。我们的数据表明Manf在调节果蝇UPR中的作用。
Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR.