TAR DNA 结合蛋白 43 可被肠道病毒 A71 的蛋白酶 3C 切割。
TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71.
机构信息
Department of Cell Biology, Harbin Medical University, Harbin, 150081, China.
Department of Microbiology, Harbin Medical University, Harbin, 150081, China.
出版信息
Virol Sin. 2021 Feb;36(1):95-103. doi: 10.1007/s12250-020-00262-x. Epub 2020 Jul 21.
Enterovirus A71 (EV-A71) is one of the etiological pathogens leading to hand, foot, and mouth disease (HFMD), which can cause severe neurological complications. The neuropathogenesis of EV-A71 infection is not well understood. The mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, whether TDP-43 was impacted by EV-A71 infection is unknown. This study demonstrated that TDP-43 was cleaved during EV-A71 infection. The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection. TDP-43 is cleaved by viral protease 3C between the residues 331Q and 332S, while mutated TDP-43 (Q331A) was not cleaved. In addition, mutated 3C which lacks the protease activity failed to induce TDP-43 cleavage. We also found that TDP-43 was translocated from the nucleus to the cytoplasm, and the mislocalization of TDP-43 was induced by viral protease 2A rather than 3C. Taken together, we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection, implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71infection.
肠道病毒 A71（EV-A71）是引起手足口病（HFMD）的病因之一，可导致严重的神经并发症。EV-A71 感染的神经发病机制尚不清楚。TAR DNA 结合蛋白 43（TDP-43）的定位错误和聚集是肌萎缩侧索硬化症（ALS）的病理标志。然而，EV-A71 感染是否会影响 TDP-43 尚不清楚。本研究表明，EV-A71 感染时 TDP-43 被切割。由于病毒感染，TDP-43 的切割需要 EV-A71 复制，而不是激活的半胱天冬酶。TDP-43 在 331Q 和 332S 残基之间被病毒蛋白酶 3C 切割，而突变的 TDP-43（Q331A）则不能被切割。此外，缺乏蛋白酶活性的突变 3C 不能诱导 TDP-43 切割。我们还发现 TDP-43 从核内易位到细胞质，TDP-43 的定位错误是由病毒蛋白酶 2A 而不是 3C 诱导的。总之，我们证明了 TDP-43 在 EV-A71 感染期间被病毒蛋白酶切割并易位到细胞质中，这表明 TDP-43 可能参与了 EV-A71 感染的发病机制。
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