Analysis of the molecular mechanism of LAPosome formation and maturation in macrophages

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K06641
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tottori University
• Principal Investigator: HATSUZAWA Kiyotaka 鳥取大学, 医学部, 教授 (20256655)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: ファゴサイトーシス / phagosome / LAP / LAPosome / SNARE蛋白質 / マクロファージ / MORN2 / LC3

Outline of Final Research Achievements

In this study, we established macrophages (MΦ) that overexpressed the LAP-related factor MORN2 and analyzed LAPosome formation and maturation. Using the MΦ that further co-expressed the SNARE protein SNAP23, we found that (1) SNAP23 is involved in LAPosome formation and (2) is more localized at LAPosome than usual. As a result of investigating the effects of phosphorylation of Ser95 of SNAP23, we found that (3) the phosphorylation of SNAP23 has no effect on LAPosome formation, and that (4) phosphorylated SNAP23 is involved in promoting LAPosome maturation.
Next, by analyzing of proteins that interact with MORN2, we identified (5) PI4 kinase A (PI4KA) as a protein that interacts with MORN2. (6) When MΦ was treated with a selective inhibitor of PI4KA, LAPosome formation was significantly enhanced. These results indicate that LAPosome formation is partially suppressed by PI4KA activity, but LAPosome formation may be promoted when PI4KA is inactivated by interaction with MORN2.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ファゴサイトーシスの一種LAPでは、貪食した異物の分解の程度が厳密に制御され、代謝・再利用あるいは抗原提示への利用に振り分けられるが、その機構は未解明である。これらは生体の恒常性維持や防御機構に重要な反応であり、LAPすなわち「LAPosomeの形成と成熟化の分子機構」の解明は急務である。本研究では、SNAP23とそのリン酸化の関与、そしてMORN2と相互作用するPI4キナーゼＡの関与を明らかにした。これらの成果は、LAP機構の理解に大きく貢献するとともに、LAP機能の不全で発症する自己免疫疾患などの治療法開発や創薬に資する可能性がある。