Elucidation of the regulatory mechanism of integrin-harboring vesicles for the suppression of pathogenic vesicles

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07331
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kansai Medical University
• Principal Investigator: KONDO Naoyuki 関西医科大学, 医学部, 講師 (30570840)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: インテグリン / 小胞輸送 / 一分子計測 / LFA1 / inside-out / outside-in / リンパ球

Outline of Final Research Achievements

Leukocyte integrin LFA1, a causative molecule for immune-related disease, plays a vital role in cell-cell interactions; however, how LFA1 accumulates on the cell contact surface has remained elusive. In this study, we discovered for the first time that LFA1 accumulation was induced by the binding of LFA1 to its ligand ICAM1 in a positive-feedback manner. This ligand binding-dependent signaling promoted the formation of LFA1-containing vesicles, which colocalized and cotrafficked with Rab8. Deletion of Rab8 decreased the accumulation of LFA1 at the contact surface and LFA1-dependent cell adhesiveness in lymphocytes. Furthermore, ligand-dependent signaling promoted the accumulation and activation of Rabin8, an activator of Rab8, at the contact surface. Based on these results, we established a novel model for LFA1 transport and accumulation in lymphocyte adhesion.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

白血球による免疫シナプス形成を介した細胞間相互作用や, ホーミングにおける血管内皮細胞に対する白血球の即座の接着において, これまでどのようにしてLFA1が素早く接着面に蓄積し接着を誘導するのかは不明であったが, LFA1-ICAM1結合に誘導される正の協同性を伴うLFA1蓄積経路の存在の解明により, そのLFA1制御メカニズムの一端が明らかになった. また, LFA1輸送におけるRabin8-Rab8経路の関与の解明は新規免疫関連疾患制御薬剤の開発や,インテグリンを含んで排出されるがん転移を担う細胞外小胞やウイルス等の産生・輸送制御法の開発にも繋がることが期待される.