RAF kinases are stabilized and required for dendritic cell differentiation and function
RAF kinases are stabilized and required for dendritic cell differentiation and function
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DOI：
10.1038/s41418-019-0416-4
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发表时间：
2019-09
影响因子：
12.4
通讯作者：
Kristina Riegel;J. Schlöder;Marco Sobczak;H. Jonuleit;B. Thiede;H. Schild;K. Rajalingam
中科院分区：
文献类型：
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作者：
Kristina Riegel;J. Schlöder;Marco Sobczak;H. Jonuleit;B. Thiede;H. Schild;K. Rajalingam
RAF 激酶（ARAF、BRAF 和 CRAF）是高度保守的酶，在 RAS 激活后触发 RAF-MEK1/2-ERK1/2 (MAPK) 通路。尽管临床兴趣巨大，但人们对 RAF 在介导免疫反应中的作用知之甚少。在这里，我们研究了 RAF 激酶和 MEK1/2 在树突状细胞 (DC) 中的作用，树突状细胞是 T 细胞介导的抗肿瘤免疫反应和适应性免疫系统的中央调节因子。我们证明 RAF 激酶在 DC 分化过程中具有活性并稳定在其蛋白质水平。抑制 RAF 激酶而不是 MEK1/2 会损害小鼠和人类 DC 的激活。正如预期的那样，用 RAF 抑制剂处理的 DC 在激活 T 细胞方面表现出缺陷。此外，RAF 和 MEK1/2 激酶是 CD4+T 细胞的激活和增殖直接需要的。我们的观察表明，RAF 和 MEK1/2 在调节 DC 功能中具有独立的作用，这对于临床中使用 RAF-MAPK 抑制剂具有重要意义。
RAF kinases (ARAF, BRAF, and CRAF) are highly conserved enzymes that trigger the RAF-MEK1/2-ERK1/2 (MAPK) pathway upon activation of RAS. Despite enormous clinical interest, relatively little is known on the role of RAFs in mediating immune responses. Here, we investigated the role of RAF kinases and MEK1/2 in dendritic cells (DCs), the central regulators of T cell-mediated antitumor immune responses and the adaptive immune system. We demonstrate that RAF kinases are active and stabilized at their protein levels during DC differentiation. Inhibition of RAF kinases but not MEK1/2 impaired the activation of DCs in both mice and human. As expected, DCs treated with RAF inhibitors show defects in activating T cells. Further, RAF and MEK1/2 kinases are directly required for the activation and proliferation of CD4+T cells. Our observations suggest that RAF and MEK1/2 have independent roles in regulating DC function that has important implications for administering RAF–MAPK inhibitors in the clinics.