Regulatory mechanism of mast cell degranulation by the novel Rab protein

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K09536
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Nagasaki University
• Principal Investigator: Kadowaki Tomoko 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (70336080)
• Co-Investigator(Kenkyū-buntansha): 筑波 隆幸 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (30264055)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: アレルギー / 細胞内小胞輸送 / 脱顆粒 / ケミカルメデイエーター / Rabタンパク質 / マスト細胞

Outline of Final Research Achievements

Mast cells are responsible for anaphylaxis and allergy. Rab44 is a large Rab GTPase that contains a Rab GTPase domain and some additional N-terminal domains. Here we investigated the role of Rab44 in the physiology of mast cells and in anaphylaxis. Rab44 knockdown impaired degranulation of murine bone-marrow mast cells (BMMCs). Rab44-knockout mice exhibited diminished anaphylaxis, and Rab44-knockout BMMCs showed a decrease in histamine secretion. Confocal microscopic analysis of constitutively active Rab44 mutants showed their partial translocation from lysosomes to the plasma membrane. Treatment with a Ca2+ ionophore also induced the translocation of Rab44 from lysosomes into the plasma membrane and cytosol. Mechanistically, Rab44 interacted with VAMP8, which is a v-SNARE protein, to promote degranulation. Immunohistochemical studies indicated that Rab44 was detectable by only cells in the immune-related tissues, suggesting that it is closely involved in the inflammatory response.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

近年、環境条件の悪化や生活様式の変化に伴うストレスによりアレルギー疾患に悩む人は増加している。アレルギー疾患の治療法としては「抗アレルギー薬」と呼ばれる一連の薬剤や吸入薬、外用のステロイド剤などが開発されているが、対症療法的が主流を占め、根治的な治療法の確立が期待されている。
我々の研究は、アレルギー反応の病態形成に直接関わる化学伝達物質の放出機構について新たな知見を示すものであり、今後の創薬標的としての可能性も秘めている。