Synapse - WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity

WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity Journal Article

Authors:	Trzeciak, A. J.; Liu, Z. L.; Gatie, M.; Krebs, A. S.; Saitz Rojas, W.; O’Neal, A. J.; Baako, A. K.; Wang, Z.; Nelson, J.; Miranda, I. C.; Uddin, J.; Lipshutz, A.; Xie, J.; Huang, C. L.; Saavedra, P. H. V.; Hadjantonakis, A. K.; Overholtzer, M.; Glickman, M. S.; Subramanya, A. R.; Vierbuchen, T.; Etchegaray, J. I.; Lucas, C. D.; Parkhurst, C. N.; Perry, J. S. A.
Article Title:	WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity
Abstract:	Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1riCre-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis. © The Author(s) 2025.
Keywords:	controlled study; protein expression; human cell; genetics; nonhuman; flow cytometry; animal cell; mouse; animal; cytology; metabolism; animals; mice; mice, knockout; animal tissue; gene expression; spleen; image analysis; dendritic cell; embryo; animal experiment; animal model; protein; cell differentiation; enzyme activation; drug effect; enzyme activity; mice, inbred c57bl; cell lineage; c57bl mouse; stem cell; liver; neutrophil; lung; adoptive transfer; neutrophils; hematopoietic stem cell; histiocyte; monocyte; macrophage; macrophages; homeostasis; myeloid progenitor cell; myeloid progenitor cells; knockout mouse; colony stimulating factor 1; lung alveolus macrophage; platelet count; interferon regulatory factors; inhibition; cell; erythrocyte count; cd135 antigen; eosinophil count; eosinophil; granulocyte precursor; myelopoiesis; genetic differentiation; macropinocytosis; pinocytosis; cd150 antigen; neutrophilia; cd48 antigen; macrophage colony-stimulating factor; interferon consensus sequence binding protein; interferon regulatory factor; humans; human; male; female; article; serine/threonine protein kinase wnk1; wnk lysine-deficient protein kinase 1; premature mortality; single cell rna seq; monocyte count; basophil count; wnk1 protein, mouse
Journal Title:	Nature Communications
Volume:	16
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2025-05-28
Start Page:	4945
Language:	English
DOI:	10.1038/s41467-025-59901-0
PUBMED:	40436823
PROVIDER:	scopus
PMCID:	PMC12120055
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105006852600&doi=10.1038%2fs41467-025-59901-0&partnerID=40&md5=90c5092abe0443a894e8e939de16d110
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008738) acknowledged in PubMed and PDF -- MSK corresponding authors are Alissa Trzeciak and Justin Perry -- Source: Scopus