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LncRNA ZEB1-AS1/miR-1224-5p/MAP4K4 轴调控持续性感染中 HeLa 细胞线粒体介导的细胞凋亡。

LncRNA ZEB1-AS1/miR-1224-5p / MAP4K4 axis regulates mitochondria-mediated HeLa cell apoptosis in persistent infection.

机构信息

Institute of Pathogenic Biology, Hengyang Medical School, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, P. R. China.

College of Medical Technology, Hunan Polytechnic of Environment and Biology, Hengyang, P. R. China.

出版信息

Virulence. 2022 Dec;13(1):444-457. doi: 10.1080/21505594.2022.2044666.

DOI:10.1080/21505594.2022.2044666
PMID:35266440
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8920228/
Abstract

Persistent infection of is thought to be responsible for the debilitating sequelae of blinding trachoma and infertility. Inhibition of host cell apoptosis is a persistent infection mechanism. ZEB1-AS1 is a long non-coding RNA (lncRNA), which was up-regulated in persistent infection in our previous work. In this study, we investigated the role of ZEB1-AS1 in persistent infection and the potential mechanisms. The results showed that ZEB1-AS1 was involved in the regulation of apoptosis, and targeted silencing of ZEB1-AS1 could increase the apoptosis rate of persistently infected cells. Mechanically, interference ZEB1-AS1 caused an apparent down-regulation of the Bcl-2/Bax ratio and the repression of the mitochondrial membrane potential with the remarkable release of cytochrome c, resulting in the significant elevation level of caspase-3 activation. Meanwhile, the luciferase reporter assay confirmed that ZEB1-AS1 acted as a sponge for miR-1224-5p to target MAP4K4. The regulatory effect of miR-1224-5p/MAP4K4 on persistent infection-induced antiapoptosis was regulated by ZEB1-AS1. In addition, ZEB1-AS1 inhibited the apoptosis of -infected cells by activating the MAPK/ERK pathway. In conclusion, we found a new molecular mechanism that the ZEB1-AS1/miR-1224-5p/MAP4K4 axis contributes to apoptosis resistance in persistent infection. This work may help understand the pathogenic mechanisms of persistent infection and reveal a potential therapeutic strategy for its treatment.

摘要

持续感染被认为是导致致盲性沙眼和不孕等致残后遗症的原因。抑制宿主细胞凋亡是持续感染的一种机制。ZEB1-AS1 是一种长链非编码 RNA（lncRNA），在我们之前的工作中发现其在持续感染中上调。在这项研究中，我们研究了 ZEB1-AS1 在持续感染中的作用及其潜在机制。结果表明，ZEB1-AS1 参与了细胞凋亡的调节，靶向沉默 ZEB1-AS1 可以增加持续感染细胞的凋亡率。从机制上讲，干扰 ZEB1-AS1 导致 Bcl-2/Bax 比值明显下调，线粒体膜电位受到抑制，细胞色素 c 明显释放，导致 caspase-3 激活水平显著升高。同时，荧光素酶报告基因实验证实 ZEB1-AS1 作为 miR-1224-5p 的海绵，靶向 MAP4K4。miR-1224-5p/MAP4K4 对持续感染诱导的抗细胞凋亡的调节作用受 ZEB1-AS1 调控。此外，ZEB1-AS1 通过激活 MAPK/ERK 通路抑制感染细胞的凋亡。总之，我们发现了一个新的分子机制，即 ZEB1-AS1/miR-1224-5p/MAP4K4 轴参与持续感染中的抗细胞凋亡。这项工作可能有助于理解持续感染的致病机制，并揭示其治疗的潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/3f982afec9f0/KVIR_A_2044666_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/83942851a1c0/KVIR_A_2044666_UF0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/81bb99d8e4e8/KVIR_A_2044666_F0001_OC.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/bc1455dd77ae/KVIR_A_2044666_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/3f982afec9f0/KVIR_A_2044666_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/83942851a1c0/KVIR_A_2044666_UF0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/81bb99d8e4e8/KVIR_A_2044666_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/9ba0044c08b8/KVIR_A_2044666_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/ab42950074b1/KVIR_A_2044666_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/8f93851732e6/KVIR_A_2044666_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/bc1455dd77ae/KVIR_A_2044666_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4425/8920228/3f982afec9f0/KVIR_A_2044666_F0006_OC.jpg

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