Zolotarenko Alena, Bruskin Sergey
Laboratory of Functional genomics, Vavilov Institute of General Genetics Russian Academy of Sciences, 119991 Moscow, Russia.
Int J Mol Sci. 2024 Apr 21;25(8):4545. doi: 10.3390/ijms25084545.
IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) is member of the IQGAP family of scaffold proteins, which are essential for assembling multiprotein complexes that coordinate various intracellular signaling pathways. Previous research has shown that is overexpressed in psoriatic skin lesions. Given its involvement in processes like cell proliferation and chemokine signaling, we sought to explore its molecular role in driving the psoriatic phenotype of keratinocytes. By conducting transcriptome profiling of HaCaT keratinocytes, we identified numerous psoriasis-associated pathways that were affected when was knocked down. These included alterations in NFkB signaling, EGFR signaling, activation of p38/MAPK and ERK1/ERK2, lipid metabolism, cytokine production, and the response to inflammatory cytokine stimulation. Real-time analysis further revealed changes in cell growth dynamics, including proliferation and wound healing. The balance between cell proliferation and apoptosis was altered, as were skin barrier functions and the production of IL-6 and IFNγ. Despite these significant findings, the diversity of the alterations observed in the knockdown cells led us to conclude that IQGAP3 may not be the best target for the therapeutic inhibition to normalize the phenotype of keratinocytes in psoriasis.
IQGAP3（含IQ基序的GTP酶激活蛋白3）是支架蛋白IQGAP家族的成员，该家族对于组装协调各种细胞内信号通路的多蛋白复合物至关重要。先前的研究表明，其在银屑病皮肤病变中过表达。鉴于其参与细胞增殖和趋化因子信号传导等过程，我们试图探究其在驱动角质形成细胞银屑病表型中的分子作用。通过对HaCaT角质形成细胞进行转录组分析，我们确定了在IQGAP3被敲低时受影响的众多银屑病相关通路。这些通路包括NFkB信号传导、EGFR信号传导的改变，p38/MAPK和ERK1/ERK2的激活，脂质代谢、细胞因子产生以及对炎性细胞因子刺激的反应。实时分析进一步揭示了细胞生长动力学的变化，包括增殖和伤口愈合。细胞增殖与凋亡之间的平衡发生了改变，皮肤屏障功能以及IL-6和IFNγ的产生也发生了变化。尽管有这些重要发现，但在敲低细胞中观察到的变化的多样性使我们得出结论，IQGAP3可能不是使银屑病中角质形成细胞表型正常化的治疗性抑制的最佳靶点。
