title: Direct targeting of membrane fusion by SNARE mimicry: Convergent evolution of Legionella effectors.
abstract: Legionella pneumophila, the Gram-negative pathogen causing Legionnaires' disease, infects host cells by hijacking endocytic pathways and forming a Legionella-containing vacuole (LCV) in which the bacteria replicate. To promote LCV expansion and prevent lysosomal targeting, effector proteins are translocated into the host cell where they alter membrane traffic. Here we show that three of these effectors [LegC2 (Legionella eukaryotic-like gene C2)/YlfB (yeast lethal factor B), LegC3, and LegC7/YlfA] functionally mimic glutamine (Q)-SNARE proteins. In infected cells, the three proteins selectively form complexes with the endosomal arginine (R)-SNARE vesicle-associated membrane protein 4 (VAMP4). When reconstituted in proteoliposomes, these proteins avidly fuse with liposomes containing VAMP4, resulting in a stable complex with properties resembling canonical SNARE complexes. Intriguingly, however, the LegC/SNARE hybrid complex cannot be disassembled by N-ethylmaleimide-sensitive factor. We conclude that LegCs use SNARE mimicry to divert VAMP4-containing vesicles for fusion with the LCV, thus promoting its expansion. In addition, the LegC/VAMP4 complex avoids the host's disassembly machinery, thus effectively trapping VAMP4 in an inactive state.
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637;
authors.forename: Xingqi
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
authors.forename: Partho
authors.initials: P
authors.lastname: Halder
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
authors.forename: Halenur
authors.initials: H
authors.lastname: Yavuz
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany rjahn@gwdg.de hashuman@uchicago.edu.
authors.forename: Reinhard
authors.identifier: 0000-0003-1542-3498
authors.initials: R
authors.lastname: Jahn
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637; rjahn@gwdg.de hashuman@uchicago.edu.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Shuman
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D011992:Endosomes / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D016952:Legionella pneumophila / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D008561:Membrane Fusion; D011485:Protein Binding; D050682:Q-SNARE Proteins / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D022161:Transport Vesicles / Q000378:metabolism / Q000382:microbiology; D014617:Vacuoles / Q000378:metabolism / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D050682:Q-SNARE Proteins; D050683:R-SNARE Proteins; C476456:VAMP4 protein, human
keywords: Legionella pneumophila; NSF; SNAREs; membrane fusion