Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis

Chia Lin Hsu, Weiyu Lin, Dhaya Seshasayee, Yung Hsiang Chen, Xiao Ding, Zhonghua Lin, Eric Suto, Zhiyu Huang, Wyne P. Lee, Hyunjoo Park, Min Xu, Mei Sun, Linda Rangell, Jeff L. Lutman, Sheila Ulufatu, Eric Stefanich, Cecile Chalouni, Meredith Sagolla, Lauri Diehl, Paul FielderBrian Dean, Mercedesz Balazs, Flavius Martin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Lysosomal storage diseases (LSDs) are a group of heterogeneous disorders caused by defects in lysosomal enzymes or transporters, resulting in accumulation of undegraded macromolecules or metabolites. Macrophage numbers are expanded in several LSDs, leading to histiocytosis of unknown pathophysiology. Here, we found that mice lacking the equilibrative nucleoside transporter 3 (ENT3) developed a spontaneous and progressive macrophage-dominated histiocytosis. In the absence of ENT3, defective apoptotic cell clearance led to lysosomal nucleoside buildup, elevated intralysosomal pH, and altered macrophage function. The macrophage accumulation was partly due to increased macrophage colony-stimulating factor and receptor expression and signaling secondary to the lysosomal defects. These studies suggest a cellular and molecular basis for the development of histiocytosis in several human syndromes associated with ENT3 mutations and potentially other LSDs.

Original languageEnglish
Pages (from-to)89-92
Number of pages4
JournalScience
Volume335
Issue number6064
DOIs
StatePublished - 6 Jan 2012

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