Podocytes exhibit a specialized protein quality control employing derlin-2 in kidney disease.
Podocytes exhibit a specialized protein quality control employing derlin-2 in kidney disease.
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足细胞在肾脏疾病中表现出利用 derlin-2 进行专门的蛋白质质量控制。
DOI：
10.1152/ajprenal.00691.2016
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
J. Reiser
中科院分区：
文献类型：
--
作者：
G. Ren;Nicholas J. Tardi;Fumihiko Matsuda;K. Koh;P. Ruiz;Changli Wei;M. Altintas;H. Ploegh;J. Reiser
足细胞是具有有限增殖能力的肾脏滤过屏障的终末分化细胞，并且是各种细胞应激源的主要肾小球靶。因此，足细胞有效地科普应激以避免细胞死亡并避免损害肾功能是特别重要的。内质网（ER）内不正确折叠的蛋白质与细胞损伤和细胞死亡增加有关。为了缓解ER应激，启动了蛋白质质量控制机制，如ER相关降解（ERAD）。Derlin-2是ERAD通路中重要的位错通道组分，在清除ER腔中错误折叠的糖蛋白中具有不可或缺的作用。通过将ER应激与肾脏疾病联系起来的研究，我们研究了derlin-2在足细胞对蛋白质错误折叠所致损伤的易感性中的作用。我们发现，足细胞采用derlin-2介导的ER质量控制系统，以维持细胞的稳态在小鼠和人肾小球。局灶节段性肾小球硬化（FSGS）或糖尿病肾病（DN）患者上调derlin-2表达，以响应肾小球损伤，相应的小鼠模型也是如此。在derlin-2缺陷足细胞中，阿霉素（ADR）诱导的ER功能障碍导致代偿反应丧失，并通过caspase-12依赖性途径导致严重的细胞损伤。此外，derlin-2在体外过表达减弱ADR诱导的足细胞损伤。因此，derlin-2是蛋白质质量控制机制的一部分，可以挽救肾小球损伤归因于ER中受损的蛋白质折叠途径。在体内诱导derlin-2的表达可能在肾小球疾病的预防和治疗中具有应用价值。
Podocytes are terminally differentiated cells of the kidney filtration barrier with a limited proliferative capacity and are the primary glomerular target for various sources of cellular stress. Accordingly, it is particularly important for podocytes to cope with stress efficiently to circumvent cell death and avoid compromising renal function. Improperly folded proteins within the endoplasmic reticulum (ER) are associated with increased cellular injury and cell death. To relieve ER stress, protein quality control mechanisms like ER-associated degradation (ERAD) are initiated. Derlin-2 is an important dislocation channel component in the ERAD pathway, having an indispensable role in clearing misfolded glycoproteins from the ER lumen. With studies linking ER stress to kidney disease, we investigated the role of derlin-2 in the susceptibility of podocytes to injury due to protein misfolding. We show that podocytes employ derlin-2 to mediate the ER quality control system to maintain cellular homeostasis in both mouse and human glomeruli. Patients with focal segmental glomerulosclerosis (FSGS) or diabetic nephropathy (DN) upregulate derlin-2 expression in response to glomerular injury, as do corresponding mouse models. In derlin-2-deficient podocytes, compensatory responses were lost under adriamycin (ADR)-induced ER dysfunction, and severe cellular injury ensued via a caspase-12-dependent pathway. Moreover, derlin-2 overexpression in vitro attenuated ADR-induced podocyte injury. Thus derlin-2 is part of a protein quality control mechanism that can rescue glomerular injury attributable to impaired protein folding pathways in the ER. Induction of derlin-2 expression in vivo may have applications in prevention and treatment of glomerular diseases.
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