Multidimensional endoplasmic reticulum stress sensing by IRE1

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15278
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUSAKI Motonori 徳島大学, 先端酵素学研究所, 助教 (90817040)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 小胞体ストレス応答 / ジスルフィド結合 / ミスフォールドタンパク質 / 小胞体ストレスセンサー

Outline of Final Research Achievements

In the endoplasmic reticulum (ER), insulin, immunoglobulins, and other secreted proteins are made to meet the needs of the organism through a complex process called oxidative folding. Folding can fail under the influence of various environmental perturbations, leading to ER stress. The underlying processes by which cells flexibly modulate their responses depending on the degree and type of ER stress play a key role in the onset and progression of several diseases, including cancer and diabetes, but remain unknown. This work proposes that IRE1α, a key regulator of the ER stress response, regulates cell responses by detecting and evaluating the quantity and quality of ER stress through the dynamic oligomer formation with its lumenal domain.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

小胞体ストレス応答 (UPR) の制御破綻は、がん、糖尿病、アルツハイマー病、パーキンソン病など様々な疾患の発症および進展と関連するため、IRE1αによるUPR制御の分子機構は盛んに議論されてきたが、IRE1α内腔ドメインの会合状態が様々なストレス因子の存在下でどのように変化するかは不明だった。本研究では、内腔ドメインの会合状態を定量的に分析し、ストレス依存的な内腔ドメインの多量体化動態を示し、UPR制御機構の分子レベルの理解が進んだ。今後、IRE1α内腔ドメインの多量体形成について薬剤的制御が可能になれば、UPR制御の破綻が関連する様々な疾患の新たな治療戦略確立の端緒となり得る。