Inflammasome activation by non-protein-linked GPI: elucidation of the autoinflammatory mechanism in PIGT-PNH

• Project/Area Number: 18K16097
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Murata Shogo 和歌山県立医科大学, 医学部, 助教 (80646034)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: PIGT-PNH / 蛋白欠損GPI / インフラマソーム / ＰＩＧＴ－ＰＮＨ

Outline of Final Research Achievements

PIGT-PNH is caused by germline heterozygous mutaition in PIGT gene in combination with somatic deletion of the normal PIGT gene localized on chromosome 20q. PIGT-PNH patients have clinically typical PNH, but they have in addition autoinflammatory features.Here, we focused on NLRP3 inflammasome activation as a autoinflammatory mechanism in PIGT-PNH.In PIGT mutation,non-protein-linked GPI accumulates on the cell surface. From our studies using PIGT-PNH patients' samples and PIGT-KO THP-1 cells, it is suggesuted that non-protein-linked GPI is involved in complement and inflammasome activation, causing autoinflammation in PIGT-PNH.

Academic Significance and Societal Importance of the Research Achievements

本研究では、PIGT-PNHに特異的な自己炎症症状を蛋白欠損GPIの蓄積によるNLRP3インフラマソーム活性化に起因するものと想定し、その分子機序の解明を行った。本研究の成果は今後のインフラマソーム研究において新たな知見を提供するものである。実臨床では、原因不明の自己炎症性疾患の診断に際し、PIGT-PNHを鑑別に挙げる一助となり、病型を同定することで適切な治療の提供に貢献できる。また、自己炎症性疾患の分子病態を標的とした治療法の開発にも貢献できる可能性がある。

Research Products

• [Journal Article] Soluble NKG2D Ligands Are Potential Biomarkers and Sentinels of Immune-Mediated Bone Marrow Injury in Bone Marrow Failure Syndromes. (2020)
  • Author(s): Murata S, Mushino T, Hosoi H, Kuriyama K, Nishikawa A, Nagakura S, Horikawa K, Yonemura Y, Nakakuma H, Sonoki T, Hanaoka N.
  • Journal Title: Acta Haematol. Volume: 143(1) Issue: 1 Pages: 33-39
  • DOI: 10.1159/000500657
  • Peer Reviewed / Open Access
• [Journal Article] Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation. (2019)
  • Author(s): Hochsmann B, Murakami Y, Osato M, Knaus A, Kawamoto M, Inoue N, Hirata T, Murata S, Anliker M, Eggermann T, Jager M, Floettmann R, Hollein A, Murase S, Ueda Y, Nishimura JI, Kanakura Y, Kohara N, Schrezenmeier H, Krawitz PM, Kinoshita T.
  • Journal Title: The Journal of Clinical Investigation Volume: 129 Issue: 12 Pages: 5123-5136
  • DOI: 10.1172/jci123501
  • Peer Reviewed / Open Access / Int'l Joint Research