The Legionella Anti-autophagy Effector RavZ Targets the Autophagosome via PI3P- and Curvature-Sensing Motifs.
Autophagy is a conserved membrane transport pathway used to destroy pathogenic microbes that access the cytosol of cells. The intracellular pathogen Legionella pneumophila interferes with autophagy by delivering an effector protein, RavZ, into the host cytosol. RavZ acts by cleaving membrane-conjugated Atg8/LC3 proteins from pre-autophagosomal structures. Its remarkable efficiency allows minute quantities of RavZ to block autophagy throughout the cell. To understand how RavZ targets pre-autophagosomes and specifically acts only on membrane-associated Atg8 proteins, we elucidated its structure. Revealed is a catalytic domain related in fold to Ulp family deubiquitinase-like enzymes and a C-terminal PI3P-binding module. RavZ targets the autophagosome via the PI3P-binding module and a catalytic domain helix, and it preferentially binds high-curvature membranes, intimating localization to highly curved domains in autophagosome intermediate membranes. RavZ-membrane interactions enhance substrate affinity, providing a mechanism for interfacial activation that also may be used by host autophagy proteins engaging only lipidated Atg8 proteins.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Florian A
FA
Horenkamp
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Karlina J
KJ
Kauffman
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA.
Lara J
LJ
Kohler
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA.
Racquel K
RK
Sherwood
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Kathryn P
KP
Krueger
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Vladimir
V
Shteyn
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA.
Craig R
CR
Roy
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: thomas.melia@yale.edu.
Thomas J
TJ
Melia
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: karin.reinisch@yale.edu.
Karin M
KM
Reinisch
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D007425:Intracellular Membranes / Q000378:metabolism*; D007875:Legionella; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D021381:Protein Transport
D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D018129:Phosphatidylinositol Phosphates