Analysis of the kinase-mediated regulatory mechanism of the inflammasome by a listerial virulence factor

• Project/Area Number: 24590524
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Kyoto University
• Principal Investigator: Hara Hideki 京都大学, 医学(系)研究科(研究院), 助教 (30456892)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: リステリア / インフラマソーム / 感染免疫 / 細菌感染 / リステリオリシン O

Outline of Final Research Achievements

Inflammasome, an intracellular protein complex, is activated after sensing of foreign compounds from pathogens or host danger molecules. Inflammasome activates caspase-1, a cysteine protease, to induce IL-1 and IL-18 secretion, and cell death. Some inflammasomes require adaptor molecule ASC to form the inflammasome, and we revealed that the phosphorylation of ASC acts as a molecular switch to activate inflammasome. This regulation was observed in the inflammasome activation induced by pathogenic infection including Listeria monocytogenes or Mycobacterium tuberculosis. Interestingly, the inflammasome response was detrimental to the host under Listeria infection and Listeria facilitated the response by a virulence factor.

Research Products

• [Int'l Joint Research] University of Michigan(米国)
• [Journal Article] Inactivation of the MAPK signaling pathway by Listeria monocytogenes infection promotes trophoblast giant cell death. (2015)
  • Author(s): Hashino M, Tachibana M, Nishida T, Hara H, Tsuchiya K, Mitsuyama M, Watanabe K, Shimizu T, Watarai M.
  • Journal Title: Front Microbiol Volume: 6 Pages: 1145-1145
  • DOI: 10.3389/fmicb.2015.01145
  • NAID: 120005947001
  • Peer Reviewed / Open Access
• [Journal Article] The adaptor ASC exacerbates lethal Listeria monocytogenes infection by mediating IL-18 production in an inflammasome-dependent and -independent manner. (2014)
  • Author(s): Tsuchiya K, Hara H, Fang R, Hernandez-Cuellar E, Sakai S, Daim S, Chen X, Dewamitta SR, Qu H, Mitsuyama M, Kawamura I.
  • Journal Title: European Journal of Immunology Volume: 44 Issue: 12 Pages: 3696-3707
  • DOI: 10.1002/eji.201444673
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Type I interferon signaling regulates the activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection. (2014)
  • Author(s): Fang R, Hara H, Sakai S, Hernandez-Cuellar E, Mitsuyama M, Kawamura I, Tsuchiya K.
  • Journal Title: Infect Immun. Volume: 82 Issue: 6 Pages: 2312-2317
  • DOI: 10.1128/iai.01572-14
  • Peer Reviewed
• [Journal Article] The RD1 locus in the Mycobacterium tuberculosis genome contributes to the maturation and secretion of IL-1α from infected macrophages through the elevation of cytoplasmic calcium levels and calpain activation. (2014)
  • Author(s): Yang R, Xi C, Sita DR, Sakai S, Tsuchiya K, Hara H, Shen Y, Qu H, Fang R, Mitsuyama M, Kawamura I.
  • Journal Title: Pathog Dis. Volume: 70 Issue: 1 Pages: 51-60
  • DOI: 10.1111/2049-632x.12075
  • Peer Reviewed
• [Journal Article] The inflammasome and its regulation. (2014)
  • Author(s): Tsuchiya K, Hara H.
  • Journal Title: Crit. Rev. Immunol. Volume: 34 Pages: 41-80
  • Peer Reviewed
• [Journal Article] Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. (2013)
  • Author(s): Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M.
  • Journal Title: Nat Immunol. Volume: 14 Issue: 12 Pages: 1247-1255
  • DOI: 10.1038/ni.2749
  • NAID: 120005348332
  • Peer Reviewed
• [Journal Article] Nitric oxide inhibits the NLRP3 inflammasome (2012)
  • Author(s): Hernandez-Cuellar E, Tsuchiya K, Hara H, Fang R, Sakai S, Kawamura I, Akira S, Mitsuyama M
  • Journal Title: J Immunol. Volume: 189 Issue: 11 Pages: 2012-2012
  • DOI: 10.4049/jimmunol.1202479
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery (2012)
  • Author(s): Tanaka T., Takahashi K., Yamane M., Tomida S., Nakamura S., Oshima K., Niwa A., Nishikomori R., Kambe N., Hara H., Mitsuyama M., Morone N., Heuse J.E., Yamamoto T., Watanabe A., Sato-Otsubo A., Ozawa S., Asaka I., Heike T., Yamanaka S., Nak
  • Journal Title: Blood Volume: 120(6) Issue: 6 Pages: 1299-308
  • DOI: 10.1182/blood-2012-03-417881
  • Peer Reviewed
• [Journal Article] Listeria monocytogenes strain-specific impairment of the TetR regulator underlies the drastic increase in cyclic di-AMP secretion and beta interferon-inducing ability (2012)
  • Author(s): Yamamoto T, Hara H, Tsuchiya K, Sakai S, Fang R, Matsuura M, Nomura T, Sato F, Mitsuyama M, Kawamura I
  • Journal Title: Infect Immun Volume: 80 Issue: 7 Pages: 2323-2332
  • DOI: 10.1128/iai.06162-11
  • Peer Reviewed
• [Presentation] The Thr223 in listeriolysin O is essential for the ability to induce the inflammasome activation (2013)
  • Author(s): Hideki Hara, Kohsuke Tsuchiya, Ikuo Kawamura and Masao Mitsuyama
  • Organizer: 第86回日本細菌学会総会
  • Place of Presentation: 幕張メッセ
• [Presentation] Involvement of the domain 3 of listeriolysin O in the inflammasome activation induced by Listeria monocytogenes infection (2012)
  • Author(s): Hideki Hara, Kohsuke Tsuchiya, Ikuo Kawamura and Masao Mitsuyama
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] リステリア感染で誘導されるインフラマソーム応答における 主要病原因子listeriolysin Oの関与とその責任領域の検討 (2012)
  • Author(s): 原 英樹、土屋 晃介、河村 伊久雄、光山 正雄
  • Organizer: 第59回トキシンシンポジウム
  • Place of Presentation: 帯広 とかちプラザ
• [Presentation] リステリア感染マクロファージで誘導されるインフラマソーム応答における主要病原因子listeriolysin Oの関与とその責任領域の検討 (2012)
  • Author(s): 原 英樹、土屋 晃介、河村 伊久雄、光山 正雄
  • Organizer: 第6回細菌学若手コロッセウム
  • Place of Presentation: 八王子 大学セミナーハウス
• [Presentation] リステリア感染における主要病原因子listeriolysin O依存的なインフラマソーム応答の役割 (2012)
  • Author(s): 原 英樹、河村 伊久雄、土屋 晃介、光山 正雄
  • Organizer: 第23回日本生体防御学会学術総会
  • Place of Presentation: 品川区総合区民会館
• [Remarks] 微生物感染症学
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/doctoral_course/r-009/
• [Remarks] 微生物感染症学
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/doctoral_course/r-009/