近日，美国国立卫生研究院Paul E. Love及其研究小组发现Notch和pre-TCR通过诱导SCF亚基Fbxl1和Fbxl12协同调控胸腺细胞增殖。该项研究成果2019年8月26日在线发表在《自然—免疫学》杂志上。

研究人员发现β选择相关的增殖需要两个SCF（Skp-cullin-F-box）泛素连接酶复合物的组合活性，其包括作为底物识别亚基的F-box蛋白Fbxl1或Fbxl12。两种SCF复合物均靶向细胞周期蛋白依赖性激酶抑制蛋白Cdkn1b，从而进行多泛素化和蛋白酶体降解。研究人员发现Notch信号诱导Fbxl1的转录，而前TCR信号诱导Fbxl12的转录。因此，Notch和pre-TCR的同时传导诱导两个基因Fbxl1和Fbxl12的表达，其产物相同但相加地起作用以促进Cdkn1b的降解、细胞周期进展和β-选择的胸腺细胞的增殖。

研究人员表示，在T细胞发育过程中增殖受到严格调节，并且仅限于未成熟的CD4和CD8阴性胸腺细胞。主要的增殖事件在Tcrβ成功重排后的“β-选择”阶段开始，并由Notch和前T细胞受体（TCR）的同时信号传导引发并依赖于它们; 然而，尚不清楚这些信号如何协同促进细胞增殖。

附：英文原文

Title: Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12

Author: Bin Zhao, Kogulan Yoganathan, LiQi Li, Jan Y. Lee, Juan Carlos Ziga-Pflcker, Paul E. Love

Issue&Volume: 2019-08-26

Abstract: Proliferation is tightly regulated during T cell development, and is limited to immature CD4CD8 thymocytes. The major proliferative event is initiated at the -selection stage following successful rearrangement of Tcr, and is triggered by and dependent on concurrent signaling by Notch and the pre-T cell receptor (TCR); however, it is unclear how these signals cooperate to promote cell proliferation. Here, we found that -selection-associated proliferation required the combined activity of two Skp-cullin-F-box (SCF) ubiquitin ligase complexes that included as substrate recognition subunits the F-box proteins Fbxl1 or Fbxl12. Both SCF complexes targeted the cyclin-dependent kinase inhibitor Cdkn1b for polyubiquitination and proteasomal degradation. We found that Notch signals induced the transcription of Fbxl1, whereas pre-TCR signals induced the transcription of Fbxl12. Thus, concurrent Notch and pre-TCR signaling induced the expression of two genes, Fbxl1 and Fbxl12, whose products functioned identically but additively to promote degradation of Cdkn1b, cell cycle progression, and proliferation of -selected thymocytes.

DOI: 10.1038/s41590-019-0469-z

Source: https://www.nature.com/articles/s41590-019-0469-z