Kim Jumi, Kwon Hyeonjoong, Kalsoom Fadia, Sajjad Muhammad Azhar, Lee Hyun Woong, Lim Jin Hong, Jung Jaesung, Chwae Yong-Joon, Park Sun, Shin Ho-Joon, Kim Kyongmin
Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Korea.
Department of Biomedical Science, Graduate School of Ajou University, Suwon 16499, Korea.
Microorganisms. 2022 Feb 23;10(3):498. doi: 10.3390/microorganisms10030498.
Ca/calmodulin-dependent protein kinase II (CaMKII), which is involved in the calcium signaling pathway, is an important regulator of cancer cell proliferation, motility, growth, and metastasis. The effects of CaMKII on hepatitis B virus (HBV) replication have never been evaluated. Here, we found that phosphorylated, active CaMKII is reduced during HBV replication. Similar to other members of the AMPK/AKT/mTOR signaling pathway associated with HBV replication, CaMKII, which is associated with this pathway, was found to be a novel regulator of HBV replication. Overexpression of CaMKII reduced the expression of covalently closed circular DNA (cccDNA), HBV RNAs, and replicative intermediate (RI) DNAs while activating AMPK and inhibiting the AKT/mTOR signaling pathway. Findings in HBx-deficient mutant-transfected HepG2 cells showed that the CaMKII-mediated AMPK/AKT/mTOR signaling pathway was independent of HBx. Moreover, AMPK overexpression reduced HBV cccDNA, RNAs, and RI DNAs through CaMKII activation. Although AMPK acts downstream of CaMKII, AMPK overexpression altered CaMKII phosphorylation, suggesting that CaMKII and AMPK form a positive feedback loop. These results demonstrate that HBV replication suppresses CaMKII activity, and that CaMKII upregulation suppresses HBV replication from cccDNA via AMPK and the AKT/mTOR signaling pathway. Thus, activation or overexpression of CaMKII may be a new therapeutic target against HBV infection.
钙/钙调蛋白依赖性蛋白激酶II（CaMKII）参与钙信号通路，是癌细胞增殖、运动、生长和转移的重要调节因子。CaMKII对乙型肝炎病毒（HBV）复制的影响从未被评估过。在这里，我们发现磷酸化的活性CaMKII在HBV复制过程中减少。与与HBV复制相关的AMPK/AKT/mTOR信号通路的其他成员类似，发现与该通路相关的CaMKII是HBV复制的新型调节因子。CaMKII的过表达降低了共价闭合环状DNA（cccDNA）、HBV RNA和复制中间体（RI）DNA的表达，同时激活了AMPK并抑制了AKT/mTOR信号通路。在转染了HBx缺陷突变体的HepG2细胞中的研究结果表明，CaMKII介导的AMPK/AKT/mTOR信号通路独立于HBx。此外，AMPK的过表达通过激活CaMKII降低了HBV cccDNA、RNA和RI DNA。尽管AMPK在CaMKII的下游起作用，但AMPK的过表达改变了CaMKII的磷酸化，表明CaMKII和AMPK形成了一个正反馈环。这些结果表明，HBV复制抑制了CaMKII的活性，而CaMKII的上调通过AMPK和AKT/mTOR信号通路从cccDNA抑制HBV复制。因此，CaMKII的激活或过表达可能是对抗HBV感染的新治疗靶点。
