Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, 30303, USA.
Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Nat Commun. 2022 Feb 3;13(1):648. doi: 10.1038/s41467-022-28316-6.
In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 (Stk11) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor (Scf) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1 proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11-soluble-Scf axis as a potential cause of DC deficiency syndromes.
在骨髓中，经典和浆细胞样树突状细胞（DC）从巨噬细胞-DC 前体（MDP）通过共同的 DC 前体（CDP）步骤发育而来。这个发育过程从它所处的龛位中获得必要的输入，其中包含内皮细胞（EC）和其他细胞类型。在这里，我们表明，在小鼠 EC 中而非 DC 中靶向敲除丝氨酸/苏氨酸激酶 11（Stk11）编码的肿瘤抑制因子肝激酶 b1（Lkb1），导致 MDP 向 CDP 的分化中断，成熟 DC 数量严重减少和自发性肿瘤发生。在野生型 EC 中，Lkb1 在苏氨酸 138 处磷酸化多嘧啶 tract 结合蛋白 1（Ptbp1），调节干细胞因子（Scf）前体 mRNA 的剪接。在缺乏 Lkb1 的情况下，Scf 的外显子 6 被剪接出来，导致 Scf 分泌的丧失。腺相关病毒介导的可溶性 Scf 或磷酸模拟突变体 Ptbp1 蛋白的基因转染，挽救了内皮细胞特异性 Stk11 敲除小鼠中 MDP 向 CDP 分化和 DC 数量减少的缺陷。总之，内皮细胞 Stk11 的表达通过调节 Scf 剪接来调节 DC 分化，标志着 Stk11-可溶性-Scf 轴作为 DC 缺乏综合征的潜在原因。
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