2023 Fiscal Year Final Research Report

Molecular basis of counteraction against the JAK-STAT signaling pathway by virus

Research Project

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Project/Area Number	21H02408
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 43020:Structural biochemistry-related
Research Institution	Hokkaido University
Principal Investigator	Ose Toyoyuki 北海道大学, 先端生命科学研究院, 教授 (80380525)
Co-Investigator(Kenkyū-buntansha)	久米田博之北海道大学, 先端生命科学研究院, 学術専門職 (00399966) 杉田征彦京都大学, 医生物学研究所, 准教授 (00734469) 于健大阪大学, 蛋白質研究所, 特任准教授(常勤) (20587860)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	JAK-STAT / 相互作用解析
Outline of Final Research Achievements	The typical activation step of the JAK-STAT pathway is the phosphorylation of a specific tyrosine residue of STAT molecules to induce reciprocal interactions between two STAT molecules, subsequent to ligand recognition by a cell surface receptor and the JAK activation. Activated STAT molecules are translocated to the nucleus to function as transcriptional factors to induce gene expression, such as for antiviral activity. Complexity of the system arises from not only the generation of both homo and hetero STAT dimers but also the presence of interactions via the N-terminal domain (NTD) of STATs. Due to the interactions between two NTDs, STAT function should be considered as an oligomer rather than a simple dimer. We presented the tetrameric form of pY-STAT in complex with DNA by cryo-EM, revealing a compact conformation that can be seamlessly transformed into a tandem DNA binding model. Based on the tetrameric structure, we can further discuss STAT targeting by virus for immune evasion.
Free Research Field	構造生物学
Academic Significance and Societal Importance of the Research Achievements	ウイルスがどの生物を宿主として選択するかを考える上で，宿主免疫系を不活化できるかどうかは非常に大きな要因である。多くのウイルスは宿主の免疫分子と結合するための蛋白質を準備し，固有の方法で免疫系を制圧する。本研究では，宿主免疫分子であるSTATとの相互作用解析，複合体構造解析に成功したため，宿主指向性を分子レベルで理解できた。この情報を用いて，将来的なウイルス変異による宿主指向性の遷移（ドリフト）を予測する研究へと展開し，新興ウイルス対策に繋がるほか，宿主免疫系を不活化しない蛋白質を組み込んだ弱毒ウイルス株設計によるワクチン開発に発展する。