Spic,即ETS家族的转录因子成员,在多种生物学过程中发挥着重要作用。Spic在胚胎干细胞(ESCs)的调控中具有关键作用,尤其是在维持其多能性方面。Spic的激活可以促进ESCs中胆碱/一碳(1C)代谢基因的表达,例如Bhmt、Bhmt2和Dmgdh,从而影响组蛋白甲基化水平,如H3R17me2和H3K4me3,这对于维持ESCs的表观遗传状态至关重要[1]。此外,Spic还参与调节B细胞发育,通过RAG介导的DNA双链断裂激活SPIC-BCLAF1转录因子复合物,从而抑制PU.1转录因子的活性,促进早期B细胞的成熟[3]。
Spic在沙门氏菌的致病性中也发挥着重要作用。沙门氏菌通过其III型分泌系统(T3SS)分泌SpiC蛋白,该蛋白可以抑制巨噬细胞的吞噬体-溶酶体融合,从而促进细菌在宿主细胞内的存活和复制。SpiC蛋白可以靶向哺乳动物Hook3蛋白的功能,从而改变细胞内转运[2]。此外,Spic还参与沙门氏菌的SPI-2 T3SS蛋白的分泌,这些蛋白对于沙门氏菌的致病性至关重要[5]。Spic的缺失会导致沙门氏菌的游动能力和在巨噬细胞内的复制能力降低,这与葡萄糖代谢有关[4]。此外,Spic还参与沙门氏菌鞭毛的合成,影响细菌的游动能力和致病性[8]。
Spic在肝细胞中的作用也得到了研究。TLR8激动剂selgantolimod(SLGN)可以调节肝细胞中Kupffer细胞的分化状态,并通过IL-6依赖性机制抑制HBV进入肝细胞。SLGN处理Kupffer细胞后,上调了单核细胞标记基因(如S100A12)的表达,并下调了与Kupffer细胞特征相关的基因(如SPIC)的表达[6]。此外,Spic在沙门氏菌疫苗研究中也具有重要作用。通过构建waaJ和spiC双缺失的沙门氏菌菌株,可以获得一种具有高免疫原性和安全性、易于区分的疫苗候选株[7]。
Spic在红细胞生成过程中也发挥着重要作用。在红细胞生成过程中,Spic表达于岛状巨噬细胞中,这些细胞构成了红细胞生成岛(EBI)的微环境。Spic的表达可以区分不同类型的岛状巨噬细胞,例如EKLF/Klf1表达的岛状巨噬细胞和Maf/Nr1h3表达的岛状巨噬细胞[9]。
综上所述,Spic在多种生物学过程中发挥着重要作用,包括维持ESCs的多能性、调节B细胞发育、沙门氏菌的致病性、肝细胞中的HBV感染、沙门氏菌疫苗研究和红细胞生成。Spic的研究有助于深入理解这些生物学过程和疾病的发生机制,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Mirzadeh Azad, Fatemeh, Struys, Eduard A, Wingert, Victoria, Stunnenberg, Hendrik G, Atlasi, Yaser. 2023. Spic regulates one-carbon metabolism and histone methylation in ground-state pluripotency. In Science advances, 9, eadg7997. doi:10.1126/sciadv.adg7997. https://pubmed.ncbi.nlm.nih.gov/37595034/
2. Shotland, Yoram, Krämer, Helmut, Groisman, Eduardo A. . The Salmonella SpiC protein targets the mammalian Hook3 protein function to alter cellular trafficking. In Molecular microbiology, 49, 1565-76. doi:. https://pubmed.ncbi.nlm.nih.gov/12950921/
3. Soodgupta, Deepti, White, Lynn S, Yang, Wei, Payton, Jacqueline E, Bednarski, Jeffrey J. . RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells through Activation of a SPIC-BCLAF1 Complex. In Cell reports, 29, 829-843.e5. doi:10.1016/j.celrep.2019.09.026. https://pubmed.ncbi.nlm.nih.gov/31644907/
4. Wang, Yaonan, Liu, Guifeng, Zhang, Jian, Geng, Shizhong, Jiao, Xin'an. 2020. WbaP is required for swarm motility and intramacrophage multiplication of Salmonella Enteritidis spiC mutant by glucose use ability. In Microbiological research, 245, 126686. doi:10.1016/j.micres.2020.126686. https://pubmed.ncbi.nlm.nih.gov/33429286/
5. Yu, Xiu-Jun, Ruiz-Albert, Javier, Unsworth, Kate E, Liu, Mei, Holden, David W. . SpiC is required for secretion of Salmonella Pathogenicity Island 2 type III secretion system proteins. In Cellular microbiology, 4, 531-40. doi:. https://pubmed.ncbi.nlm.nih.gov/12174087/
6. Roca Suarez, Armando Andres, Plissonnier, Marie-Laure, Grand, Xavier, Testoni, Barbara, Zoulim, Fabien. 2024. TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism. In Gut, 73, 2012-2022. doi:10.1136/gutjnl-2023-331396. https://pubmed.ncbi.nlm.nih.gov/38697771/
7. Zhang, Jun-Feng, Shang, Ke, Wei, Bai, Cha, Se-Yeoun, Kang, Min. 2021. Evaluation of Safety and Protective Efficacy of a waaJ and spiC Double Deletion Korean Epidemic Strain of Salmonella enterica Serovar Gallinarum. In Frontiers in veterinary science, 8, 756123. doi:10.3389/fvets.2021.756123. https://pubmed.ncbi.nlm.nih.gov/34869728/
8. Uchiya, Kei-ichi, Sugita, Asami, Nikai, Toshiaki. 2009. Involvement of SPI-2-encoded SpiC in flagellum synthesis in Salmonella enterica serovar Typhimurium. In BMC microbiology, 9, 179. doi:10.1186/1471-2180-9-179. https://pubmed.ncbi.nlm.nih.gov/19706157/
9. Mukherjee, Kaustav, Bieker, James J. 2021. Transcriptional Control of Gene Expression and the Heterogeneous Cellular Identity of Erythroblastic Island Macrophages. In Frontiers in genetics, 12, 756028. doi:10.3389/fgene.2021.756028. https://pubmed.ncbi.nlm.nih.gov/34880902/