Analysis of apoptosis induced by mycobacterial protein PE_PGRS30 via host protein PHB2

• Project/Area Number: 18K07134
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: National Center for Global Health and Medicine
• 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)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥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)
• Keywords: 結核菌 / PE_PGRS30 / マクロファージ / アポトーシス / PHB2

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.

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。

Research Products

• [Journal Article] Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference (2023)
  • Author(s): Kazunori Matsumura, Satoshi Takaki, Teruo Kirikae
  • Journal Title: Frontiers in Microbiology Volume: 14 Pages: 1080369-1080369
  • DOI: 10.3389/fmicb.2023.1080369
  • Peer Reviewed / Open Access
• [Journal Article] 結核菌タンパク質PE_PGRSの機能解析 (2020)
  • Author(s): 松村 和典, 祝 弘樹, 切替 照雄
  • Journal Title: エンドトキシン・自然免疫研究 Volume: 23 Pages: 59-63
  • NAID: 130007931267
  • Peer Reviewed / Open Access
• [Presentation] 結核菌タンパク質PE_PGRS30の機能解析 (2022)
  • Author(s): 松村和典、高木智、切替照雄
  • Organizer: 第27回日本エンドトキシン・自然免疫研究会
• [Presentation] Translocation of prohibitin 2 in macrophages is inhibited by mycobacterial protein PE_PGRS30 resulting in mitochondrial dysfunction and apoptosis. (2022)
  • Author(s): Kazunori Matsumura, Satoshi Takaki
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Mycobacterial protein PE_PGRS30 induces apoptosis via interacting prohibitin 2 (2021)
  • Author(s): Kazunori Matsumura, Satoshi Takaki
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 結核菌タンパク質PE_PGRS30 の機能解析 (2021)
  • Author(s): 松村 和典，高木 智，切替 照雄
  • Organizer: 第94 回日本細菌学会総会
• [Presentation] Analysis of mycobacterial protein PE_PGRS62 and PE_PGRS30 (2020)
  • Author(s): 松村和典、祝弘樹、切替照雄
  • Organizer: 第93回日本細菌学会総会
• [Presentation] 結核菌タンパク質PE_PGRS62とPE_PGRS30の機能解析 (2019)
  • Author(s): 松村和典、祝弘樹、切替照雄
  • Organizer: 第25回日本エンドトキシン・自然免疫研究会
• [Presentation] Mycobacterial protein PE_PGRS30 induces apoptosis through interacting host protein prohibitin 2 (2019)
  • Author(s): 松村和典、佐伯久美子、切替照雄
  • Organizer: 第92回日本細菌学会総会