Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery
Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery
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DOI：
10.1007/s12035-015-9456-z
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发表时间：
2016-10-01
影响因子：
5.1
通讯作者：
Zahedi, Rene P.
中科院分区：
文献类型：
--
作者：
Roos, Andreas;Kollipara, Laxmikanth;Zahedi, Rene P.
SIL1作为内质网伴侣BiP的核苷酸交换因子。SIL1的突变会导致marinesco - shjogren综合征（MSS），一种神经退行性疾病。此外，SIL1在肌萎缩性侧索硬化症（ALS）病因病理学中的特殊功能被强调，从而宣布功能性SIL1- bip复合物是神经退行性疾病的调节剂。因此，SIL1的缺失与ALS的早期表现和强化的疾病进展有关。由于缺乏合适的体外模型，导致MSS神经退行性变以及在ALS等其他疾病中引发神经退行性变的确切细胞病理生理机制仍然难以捉摸。我们发现，人胚胎肾293 （HEK293）细胞SIL1缺失导致内质网（ER）的结构改变，包括核膜和线粒体变性，与MSS和ALS的病理改变非常相似。功能研究显示，蛋白转运受到干扰，细胞毒性降低，增殖和活力降低，并伴有细胞防御机制的激活，包括未折叠蛋白反应、er相关降解途径、蛋白水解以及凋亡和存活因子的表达。我们的数据还表明，参与细胞骨架组织、囊泡运输、线粒体功能和神经过程的蛋白质有助于SIL1的病理生理。在SIL1缺失的运动神经元中，属于不同功能类别的典型蛋白在SIL1缺失后的蛋白表达改变可以得到证实。我们的研究结果表明，SIL1缺失的HEK293细胞是一个合适的模型，用于鉴定由SIL1表达水平调节的蛋白，并有助于MSS和其他疾病（如ALS）的神经退行性变。因此，我们的综合结果指出，参与er相关蛋白加工的蛋白质之外的蛋白质受到SIL1缺失的影响。
SIL1 acts as nucleotide exchange factor for the endoplasmic reticulum chaperone BiP. Mutations of SIL1 cause Marinesco-Sjogren syndrome (MSS), a neurodegenerative disorder. Moreover, a particular function of SIL1 for etiopathology of amyotrophic lateral sclerosis (ALS) was highlighted, thus declaring the functional SIL1-BiP complex as a modifier for neurodegenerative disorders. Thereby, depletion of SIL1 was associated with an earlier manifestation and in strengthened disease progression in ALS. Owing to the absence of appropriate in vitro models, the precise cellular pathophysiological mechanisms leading to neurodegeneration in MSS and triggering the same in further disorders like ALS are still elusive. We found that SIL1 depletion in human embryonic kidney 293 (HEK293) cells led to structural changes of the endoplasmic reticulum (ER) including the nuclear envelope and mitochondrial degeneration that closely mimic pathological alterations in MSS and ALS. Functional studies revealed disturbed protein transport, cytotoxicity with reduced proliferation and viability, accompanied by activation of cellular defense mechanisms including the unfolded protein response, ER-associated degradation pathway, proteolysis, and expression of apoptotic and survival factors. Our data moreover indicated that proteins involved in cytoskeletal organization, vesicular transport, mitochondrial function, and neurological processes contribute to SIL1 pathophysiology. Altered protein expression upon SIL1 depletion in vitro could be confirmed in Sil1-deficient motoneurones for paradigmatic proteins belonging to different functional classes. Our results demonstrate that SIL1-depleted HEK293 cells are an appropriate model to identify proteins modulated by SIL1 expression level and contributing to neurodegeneration in MSS and further disorders like ALS. Thereby, our combined results point out that proteins beyond such involved ER-related protein processing are affected by SIL1 depletion.