TFEB-mediated activation of the lysosome-autophagy system affects the transduction efficiency of adeno-associated virus 2.
TFEB-mediated activation of the lysosome-autophagy system affects the transduction efficiency of adeno-associated virus 2.
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DOI：
10.1016/j.virol.2017.06.030
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发表时间：
2017-10
期刊：
影响因子：
3.7
通讯作者：
L. Popp;Eric J. Gomez;W. Orji;M. Ho;J. Suh;Laura Segatori
中科院分区：
文献类型：
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作者：
L. Popp;Eric J. Gomez;W. Orji;M. Ho;J. Suh;Laura Segatori
腺相关病毒(AAV)介导的基因转移因其安全性而成为一种有吸引力的治疗选择。然而，有效地将AAV的基因货物运送到细胞核需要避开宿主细胞屏障，包括由溶酶体-自噬系统介导的细胞清除机制。我们使用AAV血清2型来监测对AAV细胞内化的自噬反应，并表征AAV诱导的自噬激活对转基因表达的影响。我们发现AAV2内化可以诱导转录因子EB的激活，EB是自噬和溶酶体生物发生的主要调节因子，并上调溶酶体-自噬系统。我们发现，AAV2诱导的自噬激活与转基因表达的减少平行，但也增加了蛋白质聚集体的自噬清除。这些结果可以指导具有自噬调节特性的AAV载体的设计，应用范围从设计有效的基因递送载体到治疗以自噬货物积累为特征的疾病。
Adeno-associated virus (AAV)-mediated gene transfer is an appealing therapeutic option due to AAV's safety profile. Effective delivery of AAV's genetic cargo to the nucleus, however, requires evasion of host cell barriers, including cellular clearance mechanisms mediated by the lysosome-autophagy system. We used AAV serotype 2 to monitor the autophagic response to cellular internalization of AAV and to characterize the effect of AAV-induced activation of autophagy on transgene expression. We found AAV2 internalization to induce activation of transcription factor EB, a master regulator of autophagy and lysosomal biogenesis, and upregulation of the lysosome-autophagy system. We showed that AAV2-induced activation of autophagy parallels a reduction in transgene expression, but also an increase in autophagic clearance of protein aggregates. These results can inform the design of AAV vectors with autophagy-modulating properties for applications ranging from the design of efficient gene delivery vectors to the treatment of diseases characterized by accumulation of autophagic cargo.