Su Yu-Siang, Hwang Lih-Hwa, Chen Chi-Ju
Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Front Microbiol. 2021 May 7;12:664955. doi: 10.3389/fmicb.2021.664955. eCollection 2021.
Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot, and mouth disease (HFMD) in children. Its infection can lead to severe neurological diseases or even death in some cases. While being produced in a large quantity during infection, viral proteins often require the assistance from cellular chaperones for proper folding. In this study, we found that heat shock protein A6 (HSPA6), whose function in viral life cycle is scarcely studied, was induced and functioned as a positive regulator for EV-A71 infection. Depletion of HSPA6 led to the reductions of EV-A71 viral proteins, viral RNA and virions as a result of the downregulation of internal ribosomal entry site (IRES)-mediated translation. Unlike other HSP70 isoforms such as HSPA1, HSPA8, and HSPA9, which regulate all phases of the EV-A71 life, HSPA6 was required for the IRES-mediated translation only. Unexpectedly, the importance of HSPA6 in the IRES activity could be observed in the absence of viral proteins, suggesting that HSPA6 facilitated IRES activity through cellular factor(s) instead of viral proteins. Intriguingly, the knockdown of HSPA6 also caused the reduction of luciferase activity driven by the IRES from coxsackievirus A16, echovirus 9, encephalomyocarditis virus, or hepatitis C virus, supporting that HSPA6 may assist the function of a cellular protein generally required for viral IRES activities.
肠道病毒A71（EV - A71）是一种可导致儿童手足口病（HFMD）的人类病原体。其感染在某些情况下可引发严重的神经疾病甚至死亡。在感染过程中大量产生病毒蛋白时，病毒蛋白通常需要细胞伴侣蛋白的协助才能正确折叠。在本研究中，热休克蛋白A6（HSPA6）在病毒生命周期中的功能鲜有研究，我们发现它被诱导并作为EV - A71感染的正向调节因子发挥作用。HSPA6的缺失导致EV - A71病毒蛋白、病毒RNA和病毒粒子减少，这是由于内部核糖体进入位点（IRES）介导的翻译下调所致。与其他调节EV - A71生命周期所有阶段的HSP70亚型（如HSPA1、HSPA8和HSPA9）不同，HSPA6仅对IRES介导的翻译是必需的。出乎意料的是，在没有病毒蛋白的情况下也能观察到HSPA6对IRES活性的重要性，这表明HSPA6是通过细胞因子而非病毒蛋白促进IRES活性。有趣的是，敲低HSPA6也导致由柯萨奇病毒A16、埃可病毒9、脑心肌炎病毒或丙型肝炎病毒的IRES驱动的荧光素酶活性降低，这支持HSPA6可能协助病毒IRES活性通常所需的一种细胞蛋白的功能。
