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The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor

Nature Cell Biology volume 8, pages 971–977 (2006)Cite this article

Abstract

The intracellular pathogen Legionella pneumophila avoids fusion with lysosomes and subverts membrane transport from the endoplasmic reticulum to create an organelle that supports bacterial replication1,2. Transport of endoplasmic reticulum-derived vesicles to the Legionella-containing vacuole (LCV) requires bacterial proteins that are translocated into host cells by a type IV secretion apparatus called Dot/Icm3,4,5,6,7. Recent observations have revealed recruitment of the host GTPase Rab1 to the LCV by a process requiring the Dot/Icm system8,9. Here, a visual screen was used to identify L. pneumophila mutants with defects in Rab1 recruitment. One of the factors identified in this screen was DrrA, a new Dot/Icm substrate protein translocated into host cells. We show that DrrA is a potent and highly specific Rab1 guanine nucleotide-exchange factor (GEF). DrrA can disrupt Rab1-mediated secretory transport to the Golgi apparatus by competing with endogenous exchange factors to recruit and activate Rab1 on plasma membrane-derived organelles. These data establish that intracellular pathogens have the capacity to directly modulate the activation state of a specific member of the Rab family of GTPases and thus further our understanding of the mechanisms used by bacterial pathogens to manipulate host vesicular transport.

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Figure 1: DrrA is translocated by L. pneumophila into host cells by a Dot/Icm-dependent process.
Figure 2: DrrA is a Rab1-specific GEF.
Figure 3: Deletion analysis reveals regions in DrrA necessary for Rab1 binding and GEF activity.
Figure 4: DrrA has the intrinsic ability to localize and recruit Rab1 to the plasma membrane.

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Acknowledgements

We thank G. Warren, A. Wandinger-Ness, W. Moss and E. Rubin for providing plasmids used in this study. This work was supported by National Institutes of Health (NIH) grants to C.R.R. (AI41699) and D.G.L. (GM56324), the Ludwig Institute for Cancer Research (D.T.), a Charles A. King Postdoctoral Fellowship (A.D.) and an NSF Predoctoral Award (A.I.).

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  1. Takahiro Murata

    Present address: Department of Pediatrics, Mizonokuchi Hospital, Teikyo University School of Medicine, 3-8-3 Mizonokuchi, Takatsuku, Kawasaki, 213-8507, Japan

Authors and Affiliations

  1. Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536, CT, USA

    Takahiro Murata, Alyssa Ingmundson & Craig R. Roy

  2. Department of Molecular Medicine, UMASS Medical School Two Biotech, 373 Plantation Street, Worcester, 01605, MA, USA

    Anna Delprato & David G. Lambright

  3. Department of Cell Biology, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536, CT, USA

    Derek K. Toomre

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Correspondence to Craig R. Roy.

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Supplementary Figures S1, S2, S3, Supplementary Table S1, S2 and Supplementary Methods. (PDF 560 kb)

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Murata, T., Delprato, A., Ingmundson, A. et al. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol 8, 971–977 (2006). https://doi.org/10.1038/ncb1463

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