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Lysosomal ATP transport mechanism and its significance
Author(s) -
Dong Xianping,
Zhu Michael,
MurrellLagnado Ruth,
Cao Qi,
Huang Peng,
Zhong Xi,
Zou Yuanjie
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.566.14
Subject(s) - lysosome , microbiology and biotechnology , cathepsin , vacuole , cathepsin d , autophagy , mannose 6 phosphate receptor , endocytic cycle , programmed cell death , exocytosis , chemistry , biology , biochemistry , cell , endocytosis , enzyme , secretion , cytoplasm , apoptosis
Lysosomes contain abundant ATP, which is released through lysosomal exocytosis following exposure to various stimuli. However, molecular mechanisms underlying lysosomal ATP accumulation and its physiological significance remain unknown. In this study, we report that SLC17A9 (also called VNUT) is highly enriched in lysosomes and functions as an ATP transporter in those organelles. SLC17A9 deficiency reduced lysosome ATP accumulation and compromised lysosome function, resulting in cell death. Interestingly, Cathepsin D, a lysosomal aspartyl protease, is inhibited by SLC17A9 deficiency. Heterologous expression of Cathepsin D successfully rescues lysosome dysfunction and cell death induced by SLC17A9 deficiency. We also show that P2X4 proteins are highly expressed in lysosomes of mammalian cells. By directly recording membrane currents from enlarged lysosomal vacuoles, we demonstrate that lysosomal P2X4 proteins form channels activated by ATP from the luminal side in a pH dependent manner. While the acidic pH at the luminal side inhibits P2X4 activity, increasing the luminal pH in the presence of ATP causes P2X4 activation. Our data suggests that SLC17A9 transports ATP into lysosomes to regulate Cathepsin D and P2X4 activity, playing an important role in lysosomal physiology and cell viability.