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Science 335 (6064): 89-92

Copyright © 2012 by the American Association for the Advancement of Science

Equilibrative Nucleoside Transporter 3 Deficiency Perturbs Lysosome Function and Macrophage Homeostasis

Chia-Lin Hsu,1 Weiyu Lin,1 Dhaya Seshasayee,1 Yung-Hsiang Chen,2 Xiao Ding,2 Zhonghua Lin,3 Eric Suto,3 Zhiyu Huang,3 Wyne P. Lee,3 Hyunjoo Park,3 Min Xu,3 Mei Sun,4 Linda Rangell,4 Jeff L. Lutman,5 Sheila Ulufatu,5 Eric Stefanich,5 Cecile Chalouni,4 Meredith Sagolla,4 Lauri Diehl,4 Paul Fielder,5 Brian Dean,2 Mercedesz Balazs,3 Flavius Martin1,*

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.

1 Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2 Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3 Translational Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4 Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
5 Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

* To whom correspondence should be addressed. E-mail: martin.flavius{at}gene.com

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