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

Int Immunol. 2017 Dec 31;29(12):551-566. doi: 10.1093/intimm/dxx063.


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, a transcription factor, 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.

Keywords: IL-33; TFEB; amino-acid transporter; inflammation; secretory granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Degranulation
  • Cell Line
  • Homeostasis
  • Inflammation / immunology*
  • Interleukin-33 / immunology
  • Lysosomes / metabolism*
  • Mast Cells / immunology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Rats
  • Receptors, IgG / metabolism
  • Secretory Vesicles / metabolism*
  • Signal Transduction


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Fcgr1 protein, mouse
  • Interleukin-33
  • Membrane Transport Proteins
  • Receptors, IgG
  • Slc15a4 protein, mouse
  • Tcfeb protein, mouse
  • Mechanistic Target of Rapamycin Complex 1