Structural insights into SetA-mediated Rab1 glucosylation and PI3P-guided localization during early Legionella infection
Year: 2026
Type: article
Abstract: The bacterial pathogen Legionella pneumophila secretes effector proteins that remodel host endomembranes to establish a replication-permissive niche known as the Legionella -containing vacuole (LCV). Among these, SetA disrupts vesicle trafficking by glucosylating the small GTPase Rab1, essential for ER-to-Golgi transport. Here, we report comprehensive structural and mechanistic insights into SetA-mediated Rab1 glucosylation and its PI3P-dependent membrane targeting. Crystal structures of its N-terminal glycosyltransferase and C-terminal lipid-binding domains, captured in multiple ligand-bound states, reveal how SetA specifically recognizes GDP-bound Rab1 and the head group of phosphatidylinositol 3-phosphate (PI3P), which is enriched on early LCV membranes. SAXS-based full-length modeling, biochemical assays, and cellular imaging analyses demonstrate that SetA integrates Rab1 modification with membrane localization, thereby perturbing Golgi integrity and ER morphology. Together, these findings define the dual structural mechanisms underlying SetA’s coordination of substrate glucosylation and membrane association, providing a spatiotemporal framework for understanding Legionella ’s early infection strategy.
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: National Research Foundation, Kookmin University, Seoul National University, Yonsei University, Sungkyunkwan University, National Cancer Center, Korea Basic Science Institute, National Research Foundation of Korea, Ministry of Science and ICT, South Korea, Directorate for Biological Sciences, Institute for Protein Research, Osaka University
OpenAlex ID: W7141095317