Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy
Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy
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DOI：
10.4161/auto.22791
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发表时间：
2013-02-01
期刊：
影响因子：
13.3
通讯作者：
Zhao, Zhendong
中科院分区：
文献类型：
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作者：
Huang, He;Kang, Rongyan;Zhao, Zhendong
丙型肝炎病毒（HCV）能够通过内质网（ER）应激诱导自噬，但确切的分子信号转导途径尚不清楚。我们发现，雷帕霉素复合物1（MTORC 1）的机制靶点的活性在Huh 7细胞中被抑制，无论是携带HCV-N（基因型1b）全基因组复制子还是感染JFH 1（基因型2a）病毒，这导致了活化的NF-51样激酶1（ULK 1），从而导致自噬。然后，我们分析了MTORC 1上游的活性，发现蛋白激酶AMP激活的α（PRKAA，包括PRKAA 1和PRKAA 2，也称为AMP激活的蛋白激酶，AMPK α）和AKT（指泛AKT，包括AKT 1 -3的三种亚型，也称为蛋白激酶B，PK B）都受到HCV感染的抑制。抑制AKT-TSC-MTORC 1通路有助于上调自噬，但抑制PRKAA下调自噬。对自噬的净效应来自AKT，其超过PRKAA的抑制效应。进一步发现HCV诱导的ER应激是抑制AKT通路的原因。二甲双胍，一种PRKAA激动剂，不仅通过激活PRKAA抑制HCV复制，如先前报道的，而且通过独立于自噬途径激活AKT。综上所述，我们的数据表明，HCV通过ER应激抑制AKT-TSC -MTORC 1通路，导致自噬，这可能有助于HCV诱导的自噬的建立。
Hepatitis C virus (HCV) is able to induce autophagy via endoplasmic reticulum (ER) stress, but the exact molecular signaling pathway is not well understood. We found that the activity of the mechanistic target of rapamycin complex 1 (MTORC1) was inhibited in Huh7 cells either harboring HCV-N (genotype 1b) full-genomic replicon or infected with JFH1 (genotype 2a) virus, which led to the activation of UNC-51-like kinase 1 (ULK1) and thus to autophagy. We then analyzed activity upstream of MTORC1, and found that both protein kinase, AMP-activated, alpha (PRKAA, including PRKAA1 and PRKAA2, also known as AMP-activated protein kinase, AMPK alpha) and AKT (refers to pan AKT, including three isoforms of AKT1-3, also known as protein kinase B, PKB) were inhibited by HCV infection. The inhibition of the AKT-TSC-MTORC1 pathway contributed to upregulating autophagy, but inhibition of PRKAA downregulated autophagy. The net effect on autophagy was from AKT, which overrode the inhibition effect from PRKAA. It was further found that HCV-induced ER stress was responsible for the inhibition of the AKT pathway. Metformin, a PRKAA agonist, inhibited HCV replication not only by activating PRKAA as previously reported, but also by activating AKT independently of the autophagy pathway. Taken together, our data suggested HCV inhibited the AKT-TSC -MTORC1 pathway via ER stress, resulting in autophagy, which may contribute to the establishment of the HCV-induced autophagy.