Analysis of IFN-inducible GTPase-dependent cell-autonomous immunity

• Project/Area Number: 15H04745
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Yamamoto Masahiro 大阪大学, 微生物病研究所, 教授 (00444521)
• Research Collaborator: SASAI Miwa
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: インターフェロン / トキソプラズマ / 病原体 / 膜破壊機構 / GTP分解酵素 / 病原体含有膜 / GBP2 / 原虫 / RabGDIa / インターフェロンγ / インターフェロンガンマ / 寄生胞

Outline of Final Research Achievements

Mammalian Atg8 homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular Gate-16, in IFN-γ-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma. Gate-16 but not LC3b specifically associated with the small GTPase Arf1 to mediate uniform distribution of interferon-inducible GTPases. The lack of GABARAPs reduced Arf1 activation, which led to formation of interferon-inducible GTPase-containing aggregates and hampered recruitment of interferon-inducible GTPases to vacuolar pathogens. Thus, GABARAPs are uniquely required for antimicrobial host defense through cytosolic distribution of interferon-inducible GTPases.

Research Products

• [Journal Article] Host immune responses to Toxoplasma gondii (2018)
  • Author(s): Sasai Miwa、Pradipta Ariel、Yamamoto Masahiro
  • Journal Title: International Immunology Volume: 30 Issue: 3 Pages: 113-119
  • DOI: 10.1093/intimm/dxy004
  • Peer Reviewed
• [Journal Article] Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense (2017)
  • Author(s): Sasai Miwa、Sakaguchi Naoya、Ma Ji Su、Nakamura Shuhei、Kawabata Tsuyoshi、Bando Hironori、Lee Youngae、Saitoh Tatsuya、Akira Shizuo、Iwasaki Akiko、Standley Daron M、Yoshimori Tamotsu、Yamamoto Masahiro
  • Journal Title: Nature Immunology Volume: 18 Issue: 8 Pages: 899-910
  • DOI: 10.1038/ni.3767
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of SPP inhibitors suppressing propagation of HCV and protozoa (2017)
  • Author(s): Hirano J, Okamoto T, Sugiyama Y, Suzuki T, Kusakabe S, Tokunaga M, Fukuhara T, Sasai M, Tougan T, Matsunaga Y, Yamashita K, Sakai Y, Yamamoto M, Horii T, Standley DM, Moriishi K, Moriya K, Koike K, Matsuura Y.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 50
  • DOI: 10.1073/pnas.1712484114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes. (2016)
  • Author(s): Man SM, Karki R, Sasai M, Place DE, Kesavardhana S, Temirov J, Frase S, Zhu Q, Malireddi RK, Kuriakose T, Peters JL, Neale G, Brown SA, Yamamoto M, Kanneganti TD.
  • Journal Title: Cell Volume: 167 Pages: 382-396
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RabGDIα is a negative regulator of interferon-γ-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii. (2015)
  • Author(s): Ohshima J, Sasai M, Liu J, Yamashita K, Ma JS, Lee Y, Bando H, Howard JC, Ebisu S, Hayashi M, Takeda K, Standley DM, Frickel EM, Yamamoto M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 33
  • DOI: 10.1073/pnas.1510031112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Interferon-induced activation of cell-autonomous immunity against vacuolar pathogens (2016)
  • Author(s): Masahiro Yamamoto
  • Organizer: The 45th Annual meeting of the Japanese Society for Immunology
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
  • Int'l Joint Research / Invited
• [Presentation] Mechanism of IFN-γ-inducible cell-autonomous immunity to intracellular pathogens (2016)
  • Author(s): Masahiro Yamamoto
  • Organizer: The 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 兵庫
  • Year and Date: 2016-09-06
  • Int'l Joint Research / Invited