2025-08-26 京都大学
<関連情報>
- https://www.kyoto-u.ac.jp/ja/research-news/2025-08-26-1
- https://www.kyoto-u.ac.jp/sites/default/files/2025-08/web_2508_Nakagawa-753b36c5afa87638d3804dbabee89f1e.pdf
- https://www.pnas.org/doi/10.1073/pnas.2420096122
レジオネラ・ニューモフィラを宿す液胞におけるホスファチジン酸産生は、インターフェロン誘導性GTPaseの認識シグナルである Phosphatidic acid production on the vacuole harboring Legionella pneumophila is a signal for recognition of interferon-induced GTPases
Hiromu Oide, Tomoko Kubori, Hiroki Nagai, +4 , and Kohei Arasaki
Proceedings of the National Academy of Sciences Published:August 8, 2025
DOI:https://doi.org/10.1073/pnas.2420096122
Significance
To engage with intracellular pathogens, cell autonomous immunity should discriminate between pathogen-occupied vacuolar membrane and host-derived organelle membrane. Therefore, revelation of how cell autonomous immunity-related molecules specifically recognize pathogen-containing vacuolar membrane is quite important for understanding of boundary between “self” and “nonself” inside the cell. Even though vacuolar pathogen, Legionella pneumophila (L. pneumophila), is known to be targeted by cell autonomous immunity-related molecules, it has been unknown how these proteins specifically recognize the L. pneumophila-occupied vacuole. In here, we demonstrate that one of the molecules, mouse guanylate-binding protein 2 (mGBP2) and hGBP1 recognizes Legionella-produced phosphatidic acid (PA) on the L. pneumophila-containing vacuole (LCV), suggesting that accumulation of PA is one of the nonself signals inside the cell.
Abstract
The interferon (IFN)-inducible GTPases play a crucial role in cell autonomous immunity against intracellular pathogens. Particularly, these GTPases directly recognize the host membrane-derived vacuole containing pathogens and subsequently destroy it. Although it has been revealed that these GTPases target the membrane of Legionella pneumophila (L. pneumophila)-containing vacuole (LCV), molecular mechanism has been totally uncleared. Here, we show that mouse guanylate-binding protein 2 (mGBP2) is specifically recruited to the LCV and subsequently ruptures it. Furthermore, we also show that mGBP2 recognizes phosphatidic acid (PA) produced by the Legionella effector Lpg2552 and fails to target the vacuole harboring Lpg2552-depleted L. pneumophila. Consistently, this strain successfully grows in cells expressing mGBP2. We additionally identified lysine 585 (K585) of mGBP2 is required for the binding to PA and K585-mutated mGBP2 fails to recognize LCV. Interestingly, this lysine residue is only conserved in GBP1 among human GBPs and the conserved lysine residue is important for PA recognition and subsequent LCV distribution. Importantly, L. pneumophila lacking Lpg2552 exhibits high resistance against IFN stimulation in THP-1-derived human macrophage.
