The mechanism of autoantibody production in IBD

• Project/Area Number: 25460946
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Oshima Shigeru 東京医科歯科大学, 医学部附属病院, 助教 (50376787)
• Co-Investigator(Kenkyū-buntansha): WATANABE Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 炎症性腸疾患 / オートファジー / 自己抗体 / クローン病 / リンパ球 / 炎症

Outline of Final Research Achievements

Polymorphisms in the human TNFAIP3 gene (which encodes A20 protein) are associated with reduced function or expression of A20 that confers susceptibility to Crohn’s disease. Autophagy plays important roles in autoantibody production. To determine whether A20 regulates autophagy in CD4 T cells, we analyzed A20 deficient CD4 T cells in vitro. We demonstrated that A20 deficient CD4 T cells exhibited reduced LC3 puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that A20 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. And also we demonstrated that RIPK3 interacts with p62 and regulates p62-LC3 complex formation.

Research Products

• [Int'l Joint Research] University of California, San Francisco(アメリカ合衆国)
• [Journal Article] TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. (2015)
  • Author(s): Matsuzawa Y, Oshima S, Takahara M, Maeyashiki C, Nemoto Y, Kobayashi M, Nibe Y, Nozaki K, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Averil Ma, Watanabe M
  • Journal Title: Autophagy Volume: 11 Pages: 1052-1062
  • DOI: 10.1080/15548627.2015.1055439
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. (2015)
  • Author(s): Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, Ma A.
  • Journal Title: Nat Immunol Volume: 16 Pages: 618-27
  • DOI: 10.1038/ni.3172
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RIPK3 regulates p62- LC3 complex formation via the caspase-8-dependent cleavage of p62 (2015)
  • Author(s): Y. Matsuzawa , S. Oshima, Y. Nibe, M.Kobayashi, C. Maeyashiki, Y. Nemoto, T. Nagaishi, R. Okamoto R, K. Tsuchiya, T. Nakamura, M. Watanabe.
  • Journal Title: Biochem Biophys Res Commun. Volume: 456(1) Pages: 298-304
  • DOI: 10.1016/j.bbrc.2014.11.075
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells. (2013)
  • Author(s): Callahan JA1, Hammer GE, Agelides A, Duong BH, Oshima S, North J, Advincula R, Shifrin N, Truong HA, Paw J, Barrera J, DeFranco A, Rosenblum MD, Malynn BA, Ma A.
  • Journal Title: J Immunol. Volume: 191 Pages: 535-9
  • DOI: 10.4049/jimmunol.1203335
  • Peer Reviewed
• [Journal Article] A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis. (2013)
  • Author(s): Shao L, Oshima S, Duong B, Advincula R, Barrera J, Malynn BA, Ma A.
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0062223
  • Peer Reviewed
• [Presentation] A Crohn's Disease Susceptibility Gene A20 Regulates Autophagy Dynamics in CD4 T Cells (2015)
  • Author(s): Yu Matsuzawa, Shigeru Oshima, Masanori Kobayashi, Yoichi Nibe, Chiaki Maeyashiki, Averil I. Ma, Mamoru Watanabe
  • Organizer: DDW(Digestive Disease Week)
  • Place of Presentation: Washington, DC（USA）
  • Year and Date: 2015-05-16
  • Int'l Joint Research