Lysosome biogenesis regulated by the amino-acid transporter SLC15A4 is critical for functional integrity of mast cells

Abstract

Mast cells possess specialized lysosomes, so-called secretory granules, which play a key role not only in allergic responses but also in various immune disorders. The molecular mechanisms that control secretory-granule formation are not fully understood. Solute carrier family member 15A4 (SLC15A4) is a lysosome-resident amino-acid/oligopeptide transporter that is preferentially expressed in hematopoietic-lineage cells. Here we demonstrated that SLC15A4 is required for mast-cell secretory granule homeostasis, and limits mast-cell functions and inflammatory responses by controlling the mTORC1–TFEB signaling axis. In mouse Slc15a4^−/− mast cells, diminished mTORC1 activity increased the expression and nuclear translocation of TFEB, which caused secretory granules to degranulate more potently. This alteration of TFEB function in mast cells strongly affected the FcεRI-mediated responses and IL-33–triggered inflammatory responses both in vitro and in vivo. Our results reveal a close relationship between SLC15A4 and secretory-granule biogenesis that is critical for the functional integrity of mast cells.