Migliore Loredana, Cianfanelli Valentina, Zevolini Fabrizia, Gesualdo Monica, Marzuoli Leandro, Patrussi Laura, Ulivieri Cristina, Marotta Giuseppe, Cecconi Francesco, Finetti Francesca, Baldari Cosima T
Department of Life Sciences, University of Siena, Siena, Italy.
Department of Science, University "ROMA TRE", Rome, Italy.
Sci Rep. 2024 Dec 30;14(1):31838. doi: 10.1038/s41598-024-82957-9.
The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4 T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8 T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8 T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential. These effects were recapitulated by pharmacological inhibition of the AMBRA1 activator ULK1 or its interactor PP2A. Based on the ability of PP2A to activate TFEB, we hypothesized a role for TFEB in the CTL differentiation program regulated by AMBRA1. We show that TFEB modulates RUNX3 and T-BET expression and the generation of killing-competent CTLs, and that AMBRA1 depletion, or ULK1 or PP2A inhibition, suppresses TFEB activity. These data highlight a role for AMBRA1, ULK1 and PP2A in CTL generation, mediated by TFEB, which we identify as a new pioneering transcription factor in the CTL differentiation program.
参与自噬途径的支架蛋白AMBRA1，还通过其相互作用蛋白PP2A，独立于自噬促进CD4 T细胞分化为调节性T细胞（Tregs）。在此，我们研究了AMBRA1在CD8 T细胞分化为细胞毒性T细胞（CTL）过程中的作用。CD8 T细胞中AMBRA1的缺失与驱动CTL分化的转录因子RUNX3和T-BET的表达受损相关，并导致细胞毒性潜能的获得受损。AMBRA1激活剂ULK1或其相互作用蛋白PP2A的药理学抑制作用重现了这些效应。基于PP2A激活转录因子EB（TFEB）的能力，我们推测TFEB在由AMBRA1调节的CTL分化程序中发挥作用。我们发现，TFEB调节RUNX3和T-BET的表达以及具有杀伤能力的CTL的产生，并且AMBRA1的缺失、或ULK1或PP2A的抑制会抑制TFEB的活性。这些数据突出了AMBRA1、ULK1和PP2A在由TFEB介导的CTL生成中的作用，我们将TFEB确定为CTL分化程序中的一种新的先驱转录因子。
