PDE12,全称为Phosphodiesterase 12,是一种在人类细胞中编码的蛋白质,其在细胞内发挥着多种重要的生物学功能。PDE12主要存在于线粒体中,负责去除线粒体mRNA的poly(A)尾,这是线粒体基因表达调控的关键步骤。在人类线粒体中,mRNA的poly(A)尾长度对于基因表达至关重要,而PDE12通过控制poly(A)尾的长度来调节蛋白质合成,从而影响线粒体的功能和活性。
PDE12的异常表达或突变与多种疾病的发生发展密切相关。例如,研究表明,PDE12的缺失或突变会导致线粒体RNA的异常polyadenylation,进而影响线粒体蛋白质的合成和功能,最终导致多种线粒体疾病的发生,如新生儿线粒体疾病[1]。此外,PDE12的缺失或突变还会导致线粒体DNA编码的tRNA的异常polyadenylation,进而影响线粒体蛋白质的合成和功能,最终导致细胞死亡[2]。
除了在细胞内的生物学功能,PDE12还在免疫系统中发挥着重要作用。研究表明,PDE12是2',5'-oligoadenylate synthetase (OAS)和RNase-L途径中的一个关键调节因子,该途径是干扰素(IFN)介导的抗病毒防御的主要效应臂[3]。PDE12的缺失或突变会导致OAS/RNase-L途径的过度激活,从而提高细胞对病毒的抵抗力[3]。
此外,PDE12还与多种疾病的发生发展密切相关。研究表明,PDE12的表达与1型糖尿病的发生发展相关[4]。PDE12的表达还与乳腺癌的预后相关,PDE12的高表达与乳腺癌患者的较差预后相关[5]。此外,PDE12的表达还与病毒感染相关,如牛瘟病毒(PPRV)感染后,PDE12的表达显著升高,从而降低细胞对病毒的抵抗力[6]。
综上所述,PDE12是一种在细胞内发挥多种重要生物学功能的蛋白质,其异常表达或突变与多种疾病的发生发展密切相关。PDE12的研究有助于深入理解线粒体基因表达调控的机制,以及免疫系统的功能,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Van Haute, Lindsey, Páleníková, Petra, Tang, Jia Xin, Taylor, Robert W, Minczuk, Michal. 2024. Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease. In EMBO molecular medicine, 17, 193-210. doi:10.1038/s44321-024-00172-5. https://pubmed.ncbi.nlm.nih.gov/39567835/
2. Yu, Chenxiao, Tigano, Marco, Seifert, Erin L. 2024. PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival. In EMBO molecular medicine, 17, 3-5. doi:10.1038/s44321-024-00171-6. https://pubmed.ncbi.nlm.nih.gov/39567836/
3. Wood, Edgar R, Bledsoe, Randy, Chai, Jing, Xia, Bing, Dickson, Hamilton. 2015. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors. In The Journal of biological chemistry, 290, 19681-96. doi:10.1074/jbc.M115.653113. https://pubmed.ncbi.nlm.nih.gov/26055709/
4. Santos, Aritania Sousa, Cunha-Neto, Edécio, Gonfinetti, Nelson Vinicius, Chevillard, Christophe, da Silva, Maria Elizabeth Rossi. 2022. Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes. In Frontiers in immunology, 12, 765264. doi:10.3389/fimmu.2021.765264. https://pubmed.ncbi.nlm.nih.gov/35058920/
5. Xia, Man-Zhi, Dong, Shu-Feng, Wang, Chun-Lei. 2025. Oxidative phosphorylation-related genes for prognosis and tumor microenvironment in breast cancer. In Translational cancer research, 14, 497-511. doi:10.21037/tcr-24-1181. https://pubmed.ncbi.nlm.nih.gov/39974386/
6. Tirumurugaan, Krishnaswamy Gopalan, Pawar, Rahul Mohanchandra, Dhinakar Raj, Gopal, Hammond, John A, Parida, Satya. 2020. RNAseq Reveals the Contribution of Interferon Stimulated Genes to the Increased Host Defense and Decreased PPR Viral Replication in Cattle. In Viruses, 12, . doi:10.3390/v12040463. https://pubmed.ncbi.nlm.nih.gov/32325933/