| Project/Area Number |
18K07134
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49050:Bacteriology-related
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| Research Institution | National Center for Global Health and Medicine |
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Principal Investigator |
MATSUMURA Kazunori 国立研究開発法人国立国際医療研究センター, その他部局等, 研究員 (70537670)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 結核菌 / PE_PGRS30 / マクロファージ / アポトーシス / PHB2 |
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| Outline of Final Research Achievements |
Ectopic expression of Mycobacterial protein PE_PGRS30 resulted in apoptotic cell death. We identified Prohibitin 2 (PHB2) as a candidate for interaction with PE_PGRS30. PE_PGRS30 and PHB2 were found to bind through the PGRS domain and mitochondrial target sequence, respectively. Recombinant PE_PGRS30 protein induced apoptosis in mouse alveolar macrophages. PE_PGRS30 and PHB2 co-localized via the PGRS domain in cells. PE_PGRS30 did not localize to mitochondria but co-localized with lysosomes. PHB2 have pivotal roles in structural maintenance of mitochondria by protecting OPA1, a mitochondrial structural protein, from processing, but when the PGRS domain was added to cells, cleavage of OPA1 occurred. These findings suggest that PE_PGRS30 functions by binding to intracellular PHB2 via the PGRS domain, translocating PHB2 to lysosomes for degradation, reducing the amount of PHB2 in mitochondria, and inducing apoptosis.
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| Academic Significance and Societal Importance of the Research Achievements |
結核菌が誘導する細胞死で、これまで明らかにされてきたのは外因性、すなわちリガンド-受容体の結合により産生されるTNFによりアポトーシスが誘導される機構であり、内因性細胞死の誘導機構は、ほぼ未知のままであった。今回我々は宿主側の標的因子を同定したことから、結核菌から分泌されミトコンドリアを介して感染細胞を死に至らしめる機構を初めて明らかにした。
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