Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.
Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.
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人类疱疹病毒 8 ORF57 蛋白能够减少 TDP-43 病理：网络分析确定了相互作用的途径。
DOI：
10.1093/hmg/ddad122
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发表时间：
2023
影响因子：
3.5
通讯作者：
Wolozin,Benjamin
中科院分区：
文献类型：
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作者：
Webber,ChelseaJ;Murphy,CarolineN;Rondón-Ortiz,AlejandroN;vanderSpek,SophieJF;Kelly,ElenaX;Lampl,NoahM;Chiesa,Giulio;Khalil,AhmadS;Emili,Andrew;Wolozin,Benjamin
TAR DNA结合蛋白43 kDa（TDP-43）的聚集被认为是肌萎缩侧索硬化症和某些额颞痴呆症的病理生理学驱动因素。TDP-43通常是一种核蛋白，其在神经元中易位至细胞质，并且在激活整合应激反应（ISR）时可以形成不溶性聚集体。病毒进化到控制ISR。在疱疹病毒8型的情况下，蛋白ORF 57的作用是结合蛋白激酶R，抑制eIF 2 α的磷酸化并减少ISR的活化。我们假设ORF 57也可能具有抑制TDP-43聚集的能力。ORF 57在神经元SH-SY 5 Y系中表达，并表征其对TDP-43聚集的影响。我们报道ORF 57抑制TDP-43聚集55%，并使现有TDP-43颗粒的分散率增加2.45倍。这些变化与细胞死亡减少50%有关。进行蛋白质组学研究以鉴定ORF 57的蛋白质相互作用网络。我们观察到ORF 57直接结合TDP-43，并与ISR的许多组分相互作用，包括已知可减少TDP-43聚集的蛋白质稳定机制的元件。我们提出，设计用于抑制慢性ISR的病毒蛋白可以被工程化以去除聚集的蛋白并抑制慢性ISR。
Aggregation of TAR DNA-binding protein 43 kDa (TDP-43) is thought to drive the pathophysiology of amyotrophic lateral sclerosis and some frontotemporal dementias. TDP-43 is normally a nuclear protein that in neurons translocates to the cytoplasm and can form insoluble aggregates upon activation of the integrated stress response (ISR). Viruses evolved to control the ISR. In the case of Herpesvirus 8, the protein ORF57 acts to bind protein kinase R, inhibit phosphorylation of eIF2α and reduce activation of the ISR. We hypothesized that ORF57 might also possess the ability to inhibit aggregation of TDP-43. ORF57 was expressed in the neuronal SH-SY5Y line and its effects on TDP-43 aggregation characterized. We report that ORF57 inhibits TDP-43 aggregation by 55% and elicits a 2.45-fold increase in the rate of dispersion of existing TDP-43 granules. These changes were associated with a 50% decrease in cell death. Proteomic studies were carried out to identify the protein interaction network of ORF57. We observed that ORF57 directly binds to TDP-43 as well as interacts with many components of the ISR, including elements of the proteostasis machinery known to reduce TDP-43 aggregation. We propose that viral proteins designed to inhibit a chronic ISR can be engineered to remove aggregated proteins and dampen a chronic ISR.