Shetty Ankitha, Bhosale Santosh D, Tripathi Subhash Kumar, Buchacher Tanja, Biradar Rahul, Rasool Omid, Moulder Robert, Galande Sanjeev, Lahesmaa Riitta
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.
InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland.
ACS Omega. 2021 Sep 16;6(38):24834-24847. doi: 10.1021/acsomega.1c03681. eCollection 2021 Sep 28.
Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among the latter, FOSL1 and FOSL2 modulate the effector functions of Th17 cells. However, the molecular mechanisms underlying these effects are unclear, owing to the poorly characterized protein interaction networks of FOSL factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification-mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a significant fraction of these interactors to be associated with RNA-binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17 fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL proteins that potentially govern Th17 cell differentiation and associated pathologies.
Th17细胞功能失调与免疫缺陷和自身免疫性疾病有关。Th17细胞的分化由一个复杂的转录因子网络精心调控，其中包括激活蛋白（AP-1）家族的几个成员。在后者中，FOSL1和FOSL2调节Th17细胞的效应功能。然而，由于FOSL因子的蛋白质相互作用网络特征不佳，这些效应背后的分子机制尚不清楚。在这里，我们使用亲和纯化-质谱分析建立了人类Th17细胞中FOSL1和FOSL2的首个相互作用组。除了已知的JUN蛋白外，我们还鉴定了FOSL1和FOSL2的几个新的结合伙伴。基因本体分析发现这些相互作用蛋白中有很大一部分与RNA结合活性相关，这提示了新的机制联系。有趣的是，发现有29种蛋白质与FOSL1和FOSL2共享相互作用，其中包括Th17命运的关键调节因子。我们通过使用平行反应监测靶向质谱和其他方法进一步验证了本研究中鉴定的结合伙伴。我们的研究为FOSL蛋白基于相互作用的信号传导机制提供了关键见解，这些机制可能控制Th17细胞分化及相关病理过程。
