Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation

Qiang Zhao, Young-Min Han, Ping Song, Zhixue Liu, Zuyi Yuan and Ming-Hui Zou ()
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Qiang Zhao: Georgia State University
Young-Min Han: Georgia State University
Ping Song: Georgia State University
Zhixue Liu: Georgia State University
Zuyi Yuan: First Affiliated Hospital of Xi’an Jiaotong University
Ming-Hui Zou: Georgia State University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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 Ptbp1T138E 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.

Date: 2022
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DOI: 10.1038/s41467-022-28316-6

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