A novel regulatory mechanism of autoimmune disease pathogenesis by SLC15A4

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293090
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Toyama-Sorimachi Noriko 国立研究開発法人国立国際医療研究センター, その他部局等, その他 (30217468)
• Co-Investigator(Renkei-kenkyūsha): KOBAYASHI TOSHIHIKO 国立国際医療研究センター研究所, 分子炎症制御プロジェクト, 副プロジェクト長 (40613203) ; OKAMURA TADASHI 国立国際医療研究センター研究所, ヒト型動物開発研究室, 室長 (00333790) ; SHIMIZU YUKIKO 国立国際医療研究センター研究所, ヒト型動物開発研究室, 研究員 (00469983)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 炎症 / 自己免疫疾患 / アレルギー / トランスポーター / mTOR / Toll様受容体

Outline of Final Research Achievements

A lysosome-resident, amino acid/oligopeptide transporter, SLC15A4, plays a crucial role in the pathogenesis of inflammatory diseases through regulation of TLR7/9-mediated type I interferon (IFN-I) productions. We found in this study that SLC15A4 loss caused the accumulations of histidine and histamine in the lysosomes, which resulted in the dysregulation of lysosomal pH. Moreover, SLC15A4-deficient cells showed the decrease of vATPase and mTORC1 activities. Our results indicated that SLC15A4 is an integral part of TLR7/9-triggered inflammatory signals by engaging the lysosomal conditioning. We also found that SLC15A4 regulated mast cell’s functions through the regulation of mTORC1 activity, and played an important role in secretory granule biogenesis and allergic inflammation. These results revealed that SLC15A4-dependent regulation of mTORC1 signaling pathway has an impact not only on various immune cell functions but also on the pathogenic conditions of inflammatory diseases.

Free Research Field

免疫学