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, 13 (8), 1467-1469

Lift and Cut: Anti-host Autophagy Mechanism of Legionella Pneumophila

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Lift and Cut: Anti-host Autophagy Mechanism of Legionella Pneumophila

Supansa Pantoom et al. Autophagy.

Abstract

RavZ, an effector protein of pathogenic Legionella pneumophila, inhibits host macroautophagy/autophagy by deconjugation of lipidated LC3 proteins from phosphatidylethanolamine (PE) on the autophagosome membrane. The mechanism for how RavZ specifically recognizes and deconjugates the lipidated LC3s is not clear. To understand the structure-function relationship of LC3-deconjugation by RavZ, we prepared semisynthetic LC3 proteins modified with different fragments of PE or 1-hexadecanol (C16). We find that RavZ activity is strictly dependent on the conjugated PE structure and RavZ extracts LC3-PE from the membrane before deconjugation. Structural and biophysical analysis of RavZ-LC3 interactions suggest that RavZ initially recognizes LC3-PE on the membrane via its N-terminal LC3-interacting region (LIR) motif. RavZ specifically targets to autophagosome membranes by interaction with phosphatidylinositol 3-phosphate (PtdIns3P) via its C-terminal domain and association with membranes via the hydrophobic α3 helix. The α3 helix is involved in extraction of the PE moiety and docking of the fatty acid chains into the lipid-binding site of RavZ, which is related in structure to that of the phospholipid transfer protein Sec14. The LIR interaction and lipid binding facilitate subsequent proteolytic cleavage of LC3-PE. The findings reveal a novel mode of host-pathogen interaction.

Keywords: LC3; Legionella pneumophila; RavZ; Sec14; autophagy; crystal structure; host-pathogen interaction; lipidated proteins; native chemical ligation.

Figures

Figure 1.
Figure 1.
Schematic diagram of the anti-host autophagy mechanism of Legionella pneumophila. The bacterium injects its effector RavZ into the host cell through a type IV secretion system called Dot/Icm. RavZ targets to autophagosome membranes for LC3–PE deconjugation, thereby inhibiting autophagy. RavZ (deep teal) initially recognizes an LC3 molecule (green) on the membrane via its LIR2 motif (magenta). RavZ targets to the autophagosome membrane by interaction with PtdIns3P (orange) via its C-terminal domain and association with membranes via the α3 helix. The α3 facilitates extraction of the PE moiety (yellow) from the membrane and docking of the fatty acid chains into the lipid-binding site of RavZ. The interaction of the PE moiety with LBS and the LIR2-LC3 binding facilitate the binding of the C-terminal tail with the active site for proteolytic cleavage.

Comment on

  • Punctum to: Yang A, , Pantoom S, , Wu YW. Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. Elife 2017, 6(pii):e23905; PMID:28395732; https://doi.org/10.7554/eLife.23905

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