Zhang X, Dong X, Wang H, Li J, Yang B, Zhang J, Hua Z-C
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
1] State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life Sciences and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China [2] Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target-Pharma Laboratories Inc., Changzhou, China.
Cell Death Dis. 2014 Jun 5;5(6):e1273. doi: 10.1038/cddis.2014.198.
Non-apoptotic functions of Fas-associated protein with death domain (FADD) have been implicated in T lineage lymphocytes, but the nature of FADD-dependent non-apoptotic mechanism in early T-cell development has not been completely elucidated. In this study, we show that tissue-specific deletion of FADD in immature (CD44(-)CD25(+)) thymocytes results in severe perturbation of αβ lineage development. Meanwhile, loss of FADD signaling at a later (CD44(-)CD25(-)) developmental stage does not affect subsequent T-cell development. Collectively, our work presents that FADD deficiency induces failed survival in double-negative 4 (DN4) cells, while pre-T-cell receptor (TCR) signal remains intact. In addition, Notch signaling is positive regulated on DN4 and double-positive thymocytes in T-cell-specific FADD-knockout mice, which express higher levels of a subset of Notch-target genes, including Hes1, Deltex1 and CD25. Moreover, a transcriptional repressor of Notch1, NKAP is downregulated coupled with the loss of FADD in thymocytes and is found to associate with FADD. These data suggest that as a death receptor, FADD is also required for cell survival in β-selection as a regulator of Notch1 expression.
死亡结构域相关蛋白Fas（FADD）的非凋亡功能与T淋巴细胞谱系有关，但FADD依赖性非凋亡机制在早期T细胞发育中的本质尚未完全阐明。在本研究中，我们发现未成熟（CD44-CD25+）胸腺细胞中FADD的组织特异性缺失会导致αβ谱系发育的严重紊乱。同时，在后期（CD44-CD25-）发育阶段FADD信号的缺失并不影响随后的T细胞发育。总体而言，我们的研究表明FADD缺陷导致双阴性4（DN4）细胞存活失败，而前T细胞受体（TCR）信号保持完整。此外，在T细胞特异性FADD基因敲除小鼠的DN4和双阳性胸腺细胞中，Notch信号被正向调节，这些细胞表达更高水平的Notch靶基因子集，包括Hes1、Deltex1和CD25。此外，Notch1的转录抑制因子NKAP在胸腺细胞中随着FADD的缺失而下调，并且发现与FADD相关。这些数据表明，作为一种死亡受体，FADD在β选择过程中作为Notch1表达的调节因子对细胞存活也是必需的。
