Format

Send to

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

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

Author information

1
Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan.
2
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan.
3
Department of Infectious Disease, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan.

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, 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

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center