Critical role of WNK1 in MYC-dependent early mouse thymocyte development.
Critical role of WNK1 in MYC-dependent early mouse thymocyte development.
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WNK 1在MYC依赖性小鼠胸腺细胞发育中的关键作用
DOI：
10.7554/elife.56934
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发表时间：
2020-10-14
期刊：
影响因子：
7.7
通讯作者：
Tybulewicz VL
中科院分区：
文献类型：
--
作者：
Köchl R;Vanes L;Llorian Sopena M;Chakravarty P;Hartweger H;Fountain K;White A;Cowan J;Anderson G;Tybulewicz VL
WNK1是一种控制肾盐稳态的激酶，也调节CD4+T细胞的黏附和迁移。WNK1在胸腺细胞中高表达，由于迁移对胸腺细胞成熟很重要，我们研究了WNK1在小鼠胸腺细胞发育中的作用。我们发现WNK1对于双阴性(DN)胸腺细胞通过β选择检查点以及随后的增殖和分化为双阳性(DP)胸腺细胞是必需的。此外，我们还发现WNK1负向调节LFA1介导的黏附，正向调节CXCL12诱导的糖尿病肾病胸腺细胞的迁移。尽管如此，WNK1缺陷胸腺细胞的迁移缺陷并不是发育停滞的原因。相反，我们发现在糖尿病肾病胸腺细胞中，WNK1通过OXSR1和STK39激酶以及SLc12a2离子共转运体转导TCR前信号，这是MYC转录后上调以及随后增殖和分化为DP胸腺细胞所必需的。因此，调节离子动态平衡的途径是胸腺细胞发育的关键调节因素。
WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in mouse thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the β-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases, and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.