The role of Atg family members on autophagy independent pathway

• Project/Area Number: 18H02642
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Osaka University
• Principal Investigator: SASAI Miwa 大阪大学, 微生物病研究所, 准教授 (30631551)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: オートファジー非依存的 / インフラマソーム / 非標準オートファジー / オートファジー / Atg遺伝子 / 炎症性サイトカイン / Atg / 炎症

Outline of Final Research Achievements

Autophagy-related genes have been considered to be molecules that are responsible for the phenomenon of Autophagy. Recently, however, individual autophagy-related genes have been reported to be individually involved in biological phenomena that are completely different from the phenomenon of Autophagy. In this study, we found that Gate-16 and GABARAP, among the Atg8 family genes, are involved in the negative regulation of the caspase-11-dependent non-canonical inflammasome, which is activated upon recognition of LPS in the cell.

Academic Significance and Societal Importance of the Research Achievements

インフラマソームは細菌の出す毒素や金属・結晶などによる細胞傷害といった生体における異物や異変などを認識すると活性化し、強い炎症性サイトカインや細胞死を誘導する免疫システムであるが、その活性化は厳密に制御された状況下でないと、自己免疫疾患を誘導してしまうことが知られている。本研究では、インフラマソームの中でも細胞内LPSを認識してカスパーゼ11が活性化される非標準インフラマソームが、一部のAtg8遺伝子によって負に制御されていることを証明したことから、自己免疫疾患の発症を抑えている新たな分子を同定したことになり、この遺伝子の変異は自己免疫疾患の発症となり得ることを示した。

Research Products

• [Int'l Joint Research] Telethon Institute(イタリア)
• [Int'l Joint Research] Texas Children's Hospital/Baylor College of Medicine(米国)
• [Int'l Joint Research] Chungnam National University(韓国)
• [Journal Article] Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression. (2023)
  • Author(s): Hashizaki Emi、Sasai Miwa、Okuzaki Daisuke、Nishi Tsubasa、Kobayashi Takashi、Iwanaga Shiroh、Yamamoto Masahiro
  • Journal Title: mBio Volume: 14 Issue: 1
  • DOI: 10.1128/mbio.03256-22
  • Peer Reviewed / Open Access
• [Journal Article] TFEB-mediated lysosomal exocytosis alleviates high fat diet?induced lipotoxicity in the kidney. (2023)
  • Author(s): Nakmura J, Yamamoto T*, Takabatake Y, Namba-Hamano T, Minami S, Takahashi A, Matsuda J, Sakai S, Yonishi H, Maeda S, Matsui S, Matsui I, Hamano T, Takahashi M, Goto M, Izumi Y, Bamba T, Sasai M, Yamamoto M, Matsusaka T, Niimura F, Yanagita M, Nakamura S, Yoshimori T, Ballabio A, Isaka Y.
  • Journal Title: JCI Insight Volume: 8(4) Issue: 4
  • DOI: 10.1172/jci.insight.162498
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-Toxoplasma host defense systems and the parasitic counterdefense mechanisms (2022)
  • Author(s): Sasai Miwa、Yamamoto Masahiro
  • Journal Title: Parasitology International Volume: 89 Pages: 102593-102593
  • DOI: 10.1016/j.parint.2022.102593
  • Peer Reviewed
• [Journal Article] ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota (2021)
  • Author(s): Sup Kim, June-Young Lee, Seul Gi Shin, Jin Kyung Kim, Prashanta Silwal, Young Jae Kim, Na-Ri Shin, Pil Soo Kim, Minho Won, Sang-Hee Lee, Soo Yeon Kim, Miwa Sasai, Masahiro Yamamoto, Jin-Man Kim, Jin-Woo Bae & Eun- Kyeong Jo
  • Journal Title: Autophagy Volume: 10 Issue: 10 Pages: 2856-2857
  • DOI: 10.1080/15548627.2020.1847460
  • Peer Reviewed
• [Journal Article] Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells (2021)
  • Author(s): Sasai Miwa、Ma Ji Su、Okamoto Masaaki、Nishino Kohei、Nagaoka Hikaru、Takashima Eizo、Pradipta Ariel、Lee Youngae、Kosako Hidetaka、Suh Pann-Ghill、Yamamoto Masahiro
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 7
  • DOI: 10.1084/jem.20201763
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cell-autonomous <i>Toxoplasma</i> killing program requires Irgm2 but not its microbe vacuolar localization (2021)
  • Author(s): Pradipta Ariel、Sasai Miwa、Motani Kou、Ma Ji Su、Lee Youngae、Kosako Hidetaka、Yamamoto Masahiro
  • Journal Title: Life Science Alliance Volume: 4 Issue: 7 Pages: e202000960-e202000960
  • DOI: 10.26508/lsa.202000960
  • NAID: 120007185166
  • Peer Reviewed / Open Access
• [Journal Article] T cell-derived interferon-γ is required for host defense to (2020)
  • Author(s): Nishiyama Saishi、Pradipta Ariel、Ma Ji Su、Sasai Miwa、Yamamoto Masahiro
  • Journal Title: Parasitology International Volume: 75 Pages: 102049-102049
  • DOI: 10.1016/j.parint.2019.102049
  • Peer Reviewed / Open Access
• [Journal Article] Initial phospholipid-dependent Irgb6 targeting to Toxoplasma gondii vacuoles mediates host defense. (2019)
  • Author(s): Lee, Y., Yamada, H., Pradipta, A., Ma, J.S., Okamoto, M., Nagaoka, H., Takashima, E., Standley, D.M., Sasai, M., Takei, K., Yamamoto, M.
  • Journal Title: Life Science Alliance Volume: 3 Issue: 1 Pages: 000-000
  • DOI: 10.26508/lsa.201900549
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCR4 regulates Plasmodium development in mouse and human hepatocytes (2019)
  • Author(s): Bando Hironori、Pradipta Ariel、Iwanaga Shiroh、Okamoto Toru、Okuzaki Daisuke、Tanaka Shun、Vega-Rodr?guez Joel、Lee Youngae、Ma Ji Su、Sakaguchi Naoya、Soga Akira、Fukumoto Shinya、Sasai Miwa、Matsuura Yoshiharu、Yuda Masao、Jacobs-Lorena Marcelo、Yamamoto Masahiro
  • Journal Title: Journal of Experimental Medicine Volume: 216 Issue: 8 Pages: 1733-1748
  • DOI: 10.1084/jem.20182227
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toxoplasma Effector GRA15-Dependent Suppression of IFN-γ-Induced Antiparasitic Response in Human Neurons (2019)
  • Author(s): Bando Hironori、Lee Youngae、Sakaguchi Naoya、Pradipta Ariel、Sakamoto Ryoma、Tanaka Shun、Ma Ji Su、Sasai Miwa、Yamamoto Masahiro
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 9 Pages: 140-140
  • DOI: 10.3389/fcimb.2019.00140
  • Peer Reviewed / Open Access
• [Journal Article] GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections (2018)
  • Author(s): Kim Jin Kyung、Kim Yi Sak、Lee Hye-Mi、Jin Hyo Sun、Neupane Chiranjivi、Kim Sup、Lee Sang-Hee、Min Jung-Joon、Sasai Miwa、Jeong Jae-Ho、Choe Seong-Kyu、Kim Jin-Man、Yamamoto Masahiro、Choy Hyon E.、Park Jin Bong、Jo Eun-Kyeong
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4184-4184
  • DOI: 10.1038/s41467-018-06487-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inducible Nitric Oxide Synthase Is a Key Host Factor for Toxoplasma GRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response (2018)
  • Author(s): Bando Hironori、Lee Youngae、Sakaguchi Naoya、Pradipta Ariel、Ma Ji Su、Tanaka Shun、Cai Yihong、Liu Jianfa、Shen Jilong、Nishikawa Yoshifumi、Sasai Miwa、Yamamoto Masahiro
  • Journal Title: mBio Volume: 9 Issue: 5 Pages: 5-5
  • DOI: 10.1128/mbio.01738-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toxoplasma Effector TgIST Targets Host IDO1 to Antagonize the IFN-γ-Induced Anti-parasitic Response in Human Cells (2018)
  • Author(s): Bando Hironori、Sakaguchi Naoya、Lee Youngae、Pradipta Ariel、Ma Ji Su、Tanaka Shun、Lai De-Hua、Liu Jianfa、Lun Zhao-Rong、Nishikawa Yoshifumi、Sasai Miwa、Yamamoto Masahiro
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 2073-2073
  • DOI: 10.3389/fimmu.2018.02073
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] GABARAP Autophagy Proteins Prevent the Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock (2018)
  • Author(s): Miwa Sasai, Naoya Sakaguchi, Masahiro Yamamoto
  • Organizer: 第47回日本免疫学会学術集会