Elucidation of the spatiotemporal control mechanism of JAK3 activation to discover highly selective JAK3 inhibitors

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08474
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Shinshu University
• Principal Investigator: Amano Yuji 信州大学, 学術研究院医学系, 助教 (50624681)
• Co-Investigator(Kenkyū-buntansha): 竹下 敏一 信州大学, 学術研究院医学系, 教授 (60212023)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: JAK3 / エンドソーム / シグナル伝達

Outline of Final Research Achievements

The endosome, an acidic organelle, is a platform for endocytic trafficking and signal transduction. This study found that intercellular acidic vesicle neutralizer (IAVN)s can selectively interfere with common cytokine receptor γ chain (γc) cytokine-induced signal transduction. Our data show that JAK3 targets endosomal membranes in an acidic pH-dependent manner, which is essential for γc-cytokine-induced functional signal complex formation and signal activation. Among IAVNs, Monensin and similar ionophores were particularly effective in suppressing γc-cytokine-induced cell proliferation in vitro. Monensin exerted therapeutic effects in a collagen-induced arthritis mouse model by interfering with T helper 17 cells. Our findings help further understand the immunosuppressive mechanism of IAVNs and unveil the spatial regulation of JAK3-mediated signal transduction via endosomes.

Free Research Field

シグナル伝達

Academic Significance and Societal Importance of the Research Achievements

IAVNsの一種であるヒドロキシクロロキンは、古くから自己免疫疾患の治療薬として用いられてきた一方、その作用機序に関しては明らかにされてこなかった。本研究成果はクロロキンの作用機序解明に寄与するのみでなく、モネンシン等のキャリア型のイオノフォアの免疫抑制薬としての有用性を見出した。