Abstract
SLC17A9 (solute carrier family 17 member 9) functions as an ATP transporter in lysosomes as well as other secretory vesicles. SLC17A9 inhibition or silence leads to cell death. However, the molecular mechanisms causing cell death are unclear. In this study, we report that cell death induced by SLC17A9 deficiency is rescued by the transcription factor EB (TFEB), a master gene for lysosomal protein expression, suggesting that SLC17A9 deficiency may be the main cause of lysosome dysfunction, subsequently leading to cell death. Interestingly, Cathepsin D, a lysosomal aspartic protease, is inhibited by SLC17A9 deficiency. Heterologous expression of Cathepsin D successfully rescues lysosomal dysfunction and cell death induced by SLC17A9 deficiency. On the other hand, the activity of Cathepsin B, a lysosomal cysteine protease, is not altered by SLC17A9 deficiency, and Cathepsin B overexpression does not rescue lysosomal dysfunction and cell death induced by SLC17A9 deficiency. Our data suggest that lysosomal ATP and SLC17A9 play critical roles in lysosomal function and cell viability by regulating Cathepsin D activity.
Highlights
The solute carrier (SLC) proteins form a large family of membrane transporters located in both the plasma membrane and intracellular membranes, where they play important roles in the transport of a variety of solutes across cell membranes [1,2]
Because cell death induced by SLC17A9 inhibition or deletion was rescued by the master gene for lysosomal protein production, we suggest that lysosomes, but not other secretory vesicles, are the major organelles associated with SLC17A9 deficiency-induced cell death
Because ATP is suggested to directly activate Cathepsin D in a cell free measurement [16], and because SLC17A9 functions as a lysosomal ATP transporter, we suggest that SLC17A9 may play an essential role in regulation of proteolysis in lysosomes by maintaining the lysosomal ATP level that is required for Cathepsin D activation
Summary
The solute carrier (SLC) proteins form a large family of membrane transporters located in both the plasma membrane and intracellular membranes, where they play important roles in the transport of a variety of solutes across cell membranes [1,2]. The most recently described family member, SLC17A9, is widely expressed throughout the body [3,4] and represents a vesicular nucleotide transporter (VNUT) [5]. Increasing evidence indicates that SLC17A9 is essential for vesicular ATP accumulation and plays important roles in various systems [3,4]. Recent studies suggest that lysosomes are ATP stores in many cell types [6–8] and SLC17A9 acts as an ATP transporter responsible for the accumulation of ATP in lysosomes [9,10]. SLC17A9 deficiency leads to compromised lysosomes, subsequently causing lysosomal storage and cell death [10]. The molecular mechanisms underlying cell death induced by SLC17A9 deficiency remain largely unclear
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