Exoc7,也称为Exo70,是细胞质膜外泌体复合体(Exocyst complex)的组成部分,该复合体在细胞内囊泡与细胞膜融合过程中发挥重要作用。Exocyst complex参与了多种细胞活动,包括细胞极性、细胞迁移、纤毛生成、细胞分裂、自噬以及分泌囊泡的融合。Exoc7作为该复合体的关键成员,在维持细胞正常功能方面扮演着不可或缺的角色。其功能涉及蛋白质的定位和分泌,以及细胞信号通路的调控。
Exoc7的突变或异常表达与多种疾病的发生发展密切相关。例如,在脑发育障碍中,EXOC7基因的突变会导致严重的脑萎缩、癫痫和发育迟缓等症状[4]。此外,Exoc7的异常表达还与癌症的发生发展有关,例如,在肺癌中,EXOC7的表达水平与肿瘤的恶性程度和耐药性相关[3]。在乳腺癌中,长链非编码RNA ZNF649-AS1可以通过调控EXOC7的替代剪接来影响乳腺癌细胞对曲妥珠单抗的耐药性[5]。
研究表明,Exoc7的替代剪接在多种生物学过程中发挥着重要作用。PTBP1介导的替代剪接可以调控与细胞内转运相关的基因,如EXOC7,从而控制衰老细胞中的炎症分泌表型(SASP),抑制其促肿瘤生长的作用[1]。此外,Exoc7的替代剪接还与胰岛素调节的GLUT4外泌作用密切相关,Exoc7的缺失会导致胰岛素刺激的GLUT4外泌作用显著抑制[2]。
近年来,随着RNA表观遗传修饰研究的深入,N6-甲基腺苷(m6A)修饰在调控基因表达和生物学过程中的作用逐渐受到关注。研究发现,m6A修饰可以影响EXOC7的表达和功能。例如,m6A修饰可以导致EXOC7在蛋白质和mRNA水平的表达不一致,这可能与m6A修饰对EXOC7的调控作用有关[3]。此外,m6A修饰还可以通过影响Prpf19蛋白的泛素化降解途径来调节EXOC7的表达和功能[6]。
综上所述,Exoc7作为Exocyst complex的关键成员,在细胞内囊泡与细胞膜融合过程中发挥着重要作用。Exoc7的突变或异常表达与多种疾病的发生发展密切相关,包括脑发育障碍和癌症。此外,Exoc7的替代剪接和m6A修饰在调控基因表达和生物学过程中发挥着重要作用。深入研究Exoc7的功能和调控机制,有助于揭示其在疾病发生发展中的作用,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Georgilis, Athena, Klotz, Sabrina, Hanley, Christopher J, Zender, Lars, Gil, Jesús. . PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. In Cancer cell, 34, 85-102.e9. doi:10.1016/j.ccell.2018.06.007. https://pubmed.ncbi.nlm.nih.gov/29990503/
2. Wang, Shifeng, Crisman, Lauren, Miller, Jessica, Yu, Haijia, Shen, Jingshi. 2019. Inducible Exoc7/Exo70 knockout reveals a critical role of the exocyst in insulin-regulated GLUT4 exocytosis. In The Journal of biological chemistry, 294, 19988-19996. doi:10.1074/jbc.RA119.010821. https://pubmed.ncbi.nlm.nih.gov/31740584/
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4. Coulter, Michael E, Musaev, Damir, DeGennaro, Ellen M, Gleeson, Joseph G, Walsh, Christopher A. 2020. Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival. In Genetics in medicine : official journal of the American College of Medical Genetics, 22, 1040-1050. doi:10.1038/s41436-020-0758-9. https://pubmed.ncbi.nlm.nih.gov/32103185/
5. Dong, Huaying, Han, Jing, Chen, Xiang, Han, Mingli, Wang, Wei. 2024. LncRNA ZNF649-AS1 promotes trastuzumab resistance and TAM-dependent PD-L1 expression in breast cancer by regulating EXOC7 alternative splicing. In Archives of biochemistry and biophysics, 761, 110128. doi:10.1016/j.abb.2024.110128. https://pubmed.ncbi.nlm.nih.gov/39159899/
6. Chen, Zhefan Stephen, Huang, Xiaoying, Talbot, Kevin, Chan, Ho Yin Edwin. 2021. A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3. In Cell death & disease, 12, 136. doi:10.1038/s41419-021-03444-x. https://pubmed.ncbi.nlm.nih.gov/33542212/