Human Adenovirus Type 5 Induces Cell Lysis through Autophagy and Autophagy-Triggered Caspase Activity
Human Adenovirus Type 5 Induces Cell Lysis through Autophagy and Autophagy-Triggered Caspase Activity
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DOI：
10.1128/jvi.02032-10
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Fueyo, Juan
中科院分区：
文献类型：
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作者：
Jiang, Hong;White, Erin J.;Fueyo, Juan
溶瘤腺病毒，例如 Delta-24-RGD，是治疗脑肿瘤患者的有希望的疗法。临床试验表明，应提高这些癌症选择性腺病毒的效力，以优化治疗效果。一种潜在的策略是提高腺病毒诱导的细胞裂解的效率，这一机制尚未明确描述。在这项研究中，我们首次报道自噬在腺病毒诱导的细胞裂解中发挥作用。腺病毒感染后期，大量自噬空泡伴随着细胞结构的破坏，导致细胞裂解。尽管自噬体的形成足以进行病毒诱导的细胞裂解，但病毒通过与溶酶体融合诱导从自噬体起始到其周转的完整自噬过程。重要的是，自噬基因（ATG5 或 ATG10）的下调可以挽救受感染的细胞免遭病毒裂解。此外，自噬通过外源性 FADD/caspase 8 途径触发 caspase 活性，这也有助于腺病毒介导的细胞裂解。因此，我们的研究表明自噬和半胱天冬酶激活是腺病毒诱导细胞裂解机制的一部分，并表明对该过程的操纵是优化溶瘤腺病毒临床疗效的潜在策略。
Oncolytic adenoviruses, such as Delta-24-RGD, are promising therapies for patients with brain tumor. Clinical trials have shown that the potency of these cancer-selective adenoviruses should be increased to optimize therapeutic efficacy. One potential strategy is to increase the efficiency of adenovirus-induced cell lysis, a mechanism that has not been clearly described. In this study, for the first time, we report that autophagy plays a role in adenovirus-induced cell lysis. At the late stage after adenovirus infection, numerous autophagic vacuoles accompany the disruption of cellular structure, leading to cell lysis. The virus induces a complete autophagic process from autophagosome initiation to its turnover through fusion with the lysosome although the formation of the autophagosome is sufficient for virally induced cell lysis. Importantly, down-modulation of autophagy genes (ATG5 or ATG10) rescues the infected cells from being lysed by the virus. Moreover, autophagy triggers caspase activity via the extrinsic FADD/caspase 8 pathway, which also contributes to adenovirus-mediated cell lysis. Therefore, our study implicates autophagy and caspase activation as part of the mechanism for cell lysis induced by adenovirus and suggests that manipulation of the process is a potential strategy to optimize clinical efficacy of oncolytic adenoviruses.