Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration.
Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration.
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DOI：
10.1371/journal.ppat.1005018
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Spector SA
中科院分区：
文献类型：
--
作者：
Campbell GR;Rawat P;Bruckman RS;Spector SA
HIV Nef 通过与 beclin-1 (BECN1) 相互作用充当抗自噬成熟因子。我们报告说，巨噬细胞暴露于感染性或非感染性纯化 HIV 中会诱导 Toll 样受体 8 (TLR8) 和 BECN1 依赖性去磷酸化和 TFEB 核转位，这与自噬标记物的增加相关。对 ATG13、TFEB、TLR8 或 BECN1 的 RNA 干扰会抑制这种 HIV 诱导的自噬。然而，一旦 HIV 形成有效感染，TFEB 磷酸化和细胞质隔离就会增加，导致自噬标记物减少。此外，到感染后 7 天，自噬水平与模拟感染对照相似。相反，尽管 Nef 删除的 HIV 类似地诱导 TFEB 去磷酸化和核定位，并增加自噬，但这些水平在持续的生产性感染期间仍然升高。因此，HIV 和 TLR8 之间的相互作用充当自噬诱导的信号，该信号依赖于 TFEB 的去磷酸化和核转位。在允许感染期间，Nef 结合 BECN1，导致哺乳动物雷帕霉素靶点 (MTOR) 激活、TFEB 磷酸化和胞质隔离，以及自噬抑制。据我们所知，这是第一份关于病毒调节 TFEB 定位的报告，有助于解释 HIV 如何调节自噬以促进其自身复制和细胞存活。在基础条件下，哺乳动物雷帕霉素靶标 (MTOR) 磷酸化转录因子 EB (TFEB)，导致其滞留在细胞质中。当 MTOR 被抑制时，TFEB 去磷酸化并转移到细胞核，增加自噬和溶酶体基因表达。由于人类免疫缺陷病毒 1 型 (HIV) Nef 通过与 beclin-1 (BECN1) 相互作用充当抗自噬成熟因子，因此我们研究了 Nef 和 TFEB 在 HIV 感染人类巨噬细胞期间调节自噬的作用。我们发现，暴露于 HIV 后，巨噬细胞通过 Toll 样受体 8 (TLR8) 和 BECN1 依赖性去磷酸化和 TFEB 核转位引发自噬反应。然而，一旦 HIV 感染建立，TFEB 的磷酸化和细胞质隔离以及自噬就会恢复到感染前的水平。此外，这种逆转取决于 HIV Nef 的存在。总的来说，数据表明 HIV 和 TLR8 之间的相互作用可作为自噬诱导的信号，该信号依赖于 TFEB 的去磷酸化和核转位。一旦 HIV 建立有效感染，Nef 就会结合 BECN1，导致 MTOR 激活、TFEB 磷酸化、胞质隔离以及自噬抑制。
HIV Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1). We report that exposure of macrophages to infectious or non-infectious purified HIV induces toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB and that this correlates with an increase in autophagy markers. RNA interference for ATG13, TFEB, TLR8, or BECN1 inhibits this HIV-induced autophagy. However, once HIV establishes a productive infection, TFEB phosphorylation and cytoplasmic sequestration are increased resulting in decreased autophagy markers. Moreover, by 7 d post-infection, autophagy levels are similar to mock infected controls. Conversely, although Nef deleted HIV similarly induces TFEB dephosphorylation and nuclear localization, and increases autophagy, these levels remain elevated during continued productive infection. Thus, the interaction between HIV and TLR8 serves as a signal for autophagy induction that is dependent upon the dephosphorylation and nuclear translocation of TFEB. During permissive infection, Nef binds BECN1 resulting in mammalian target of rapamycin (MTOR) activation, TFEB phosphorylation and cytosolic sequestration, and the inhibition of autophagy. To our knowledge, this is the first report of a virus modulating TFEB localization and helps to explain how HIV modulates autophagy to promote its own replication and cell survival. Under basal conditions, the mammalian target of rapamycin (MTOR) phosphorylates transcription factor EB (TFEB) resulting in its cytoplasmic retention. When MTOR is inhibited, TFEB is dephosphorylated and translocated to the nucleus where it increases autophagy and lysosomal gene expression. As human immunodeficiency virus type 1 (HIV) Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1), we investigated the role of Nef and TFEB in the modulation of autophagy during HIV infection of human macrophages. We found that upon exposure to HIV, macrophages elicited an autophagic response through a toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB. However, once HIV infection is established, phosphorylation and cytoplasmic sequestration of TFEB as well as autophagy revert to pre-infection levels. Moreover, this reversion is dependent upon the presence of HIV Nef. Collectively, the data suggests that the interaction between HIV and TLR8 serves as a signal for autophagy induction that is dependent upon the dephosphorylation and nuclear translocation of TFEB. Once HIV establishes a productive infection, Nef binds BECN1 resulting in MTOR activation, TFEB phosphorylation and cytosolic sequestration and the inhibition of autophagy.
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