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J Biol Chem. 2019 Feb 15;294(7):2386-2396. doi: 10.1074/jbc.RA118.006226. Epub 2018 Dec 20.

Interleukin 34 (IL-34) cell-surface localization regulated by the molecular chaperone 78-kDa glucose-regulated protein facilitates the differentiation of monocytic cells.

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From the Division of Medical Bioengineering, Graduate School of Natural Science and Technology.
the Department of Applied Chemistry and Biotechnology, Faculty of Engineering, and.
the Laboratory of Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Tsushima-Naka 3-1-1, Kita-ku, Okayama 700-8530, Japan.
From the Division of Medical Bioengineering, Graduate School of Natural Science and Technology,


Interleukin 34 (IL-34) constitutes a cytokine that shares a common receptor, colony-stimulating factor-1 receptor (CSF-1R), with CSF-1. We recently identified a novel type of monocytic cell termed follicular dendritic cell-induced monocytic cells (FDMCs), whose differentiation depended on CSF-1R signaling through the IL-34 produced from a follicular dendritic cell line, FL-Y. Here, we report the functional mechanisms of the IL-34-mediated CSF-1R signaling underlying FDMC differentiation. CRIPSR/Cas9-mediated knockout of the Il34 gene confirmed that the ability of FL-Y cells to induce FDMCs completely depends on the IL-34 expressed by FL-Y cells. Transwell culture experiments revealed that FDMC differentiation requires a signal from a membrane-anchored form of IL-34 on the FL-Y cell surface, but not from a secreted form, in a direct interaction between FDMC precursor cells and FL-Y cells. Furthermore, flow cytometric analysis using an anti-IL-34 antibody indicated that IL-34 was also expressed on the FL-Y cell surface. Thus, we explored proteins interacting with IL-34 in FL-Y cells. Mass spectrometry analysis and pulldown assay identified that IL-34 was associated with the molecular chaperone 78-kDa glucose-regulated protein (GRP78) in the plasma membrane fraction of FL-Y cells. Consistent with this finding, GRP78-heterozygous FL-Y cells expressed a lower level of IL-34 protein on their cell surface and exhibited a reduced competency to induce FDMC differentiation compared with the original FL-Y cells. These results indicated a novel GRP78-dependent localization and specific function of IL-34 in FL-Y cells related to monocytic cell differentiation.


CRISPR/Cas; GRP78; Western blot; cell differentiation; cell surface protein; chaperone; colony-stimulating factor-1 receptor; cytokine; follicular dendritic cell; interleukin; interleukin 34; monocyte; plasma membrane

[Available on 2020-02-15]
[Indexed for MEDLINE]

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