Reticulon 3 attenuates the clearance of cytosolic prion aggregates by inhibiting autophagy
Reticulon 3 attenuates the clearance of cytosolic prion aggregates by inhibiting autophagy
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Reticulon 3 通过抑制自噬来减弱胞质朊病毒聚集体的清除
DOI：
10.4161/auto.7.2.14197
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发表时间：
2011-02-01
期刊：
影响因子：
13.3
通讯作者：
Xiao, Gengfu
中科院分区：
文献类型：
--
作者：
Chen, Rui;Jin, Rui;Xiao, Gengfu
自噬在靶向细胞蛋白、蛋白聚集体和细胞器降解以维持细胞生存方面起着重要作用。自噬功能障碍在与蛋白质错误折叠和聚集相关的神经退行性疾病中被广泛描述。然而，自噬在朊病毒疾病过程中的作用尚不清楚。在这里，我们发现当在小鼠神经母细胞瘤N2a细胞中表达时，细胞质PrP （cyp）聚集导致内质网应激（ER应激），网状3 （RTN3）的激活，泛素-蛋白酶体系统（UPS）的损伤，诱导自噬和凋亡。RTN3属于网状蛋白家族，在大脑中表达量最高，在内质网应激下RTN3常被激活。为了评估RTN3在涉及cyrp蛋白错误折叠的病理条件下的功能，我们在转染cyrp的细胞中敲低RTN3的表达；出乎意料的是，抑制RTN3的表达增强了cypp聚集体诱导的自噬，这一过程是由RTN3促进Bcl-2与Beclin - 1之间增强的相互作用介导的，从而增强了Bcl-2介导的对Beclin - 1依赖性自噬的抑制。此外，RTN3的下调促进了cyp聚集体的清除，使UPS的活性恢复，并减轻了内质网应激；最终，由cyp聚集体引起的细胞凋亡被抑制。综上所述，这些数据表明RTN3负性调节自噬以阻断cyp聚集体的清除，并为诱导自噬治疗朊病毒病和其他神经退行性疾病（如帕金森病（PD）、阿尔茨海默病（AD）和亨廷顿病（HD））提供了线索。
Autophagy plays an important role in targeting cellular proteins, protein aggregates and organelles for degradation for cell survival. Autophagy dysfunction has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation. However, the role of autophagy in the prion disease process is unclear. Here, we show that when expressed in mouse neuroblastoma N2a cells, cytoplasmic PrP (cyPrP) aggregates lead to endoplasmic reticulum stress (ER stress), activation of reticulon 3 (RTN3), impairment of ubiquitin-proteasome system (UPS), induction of autophagy and apoptosis. RTN3 belongs to the reticulon family with the highest expression in the brain and RTN3 is often activated under ER stress. To assess the function of RTN3 in pathological conditions involving cyPrP protein misfolding, we knocked down the expression of RTN3 in cyPrP-transfected cells; unexpectedly, the inhibition of expression of RTN3 enhances the induction of autophagy resulted from cyPrP aggregates, and the process is mediated by the enhanced interaction between Bcl-2 and Beclin 1 promoted by RTN3, which enhances Bcl-2-mediated inhibition of Beclin 1-dependent autophagy. Furthermore, downregulation of RTN3 promoted the clearance of cyPrP aggregates, allowed the activity of the UPS to resume, and alleviated ER stress; ultimately, apoptosis due to the cyPrP aggregates was inhibited. Together, these data suggest that RTN3 negatively regulates autophagy to block the clearance of cyPrP aggregates and provide a clue regarding the potential to induce autophagy for the treatment of prion disease and other neurodegenerative diseases such as Parkinson disease (PD), Alzheimer disease (AD) and Huntington disease (HD).