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Sci. Signal., 16 March 2010
Vol. 3, Issue 113, p. ra21
[DOI: 10.1126/scisignal.2000651]

RESEARCH ARTICLES

A Loss-of-Function Screen Reveals Ras- and Raf-Independent MEK-ERK Signaling During Chlamydia trachomatis Infection

Rajendra Kumar Gurumurthy1*, André P. Mäurer1*, Nikolaus Machuy1*, Simone Hess1{dagger}, Klaus P. Pleissner2, Johannes Schuchhardt3, Thomas Rudel1{ddagger}, and Thomas F. Meyer1§

1 Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
2 Core Facility Bioinformatics, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
3 MicroDiscovery GmbH, 10405 Berlin, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Hannover Medical School, 30625 Hannover, Germany.

{ddagger} Present address: Department of Microbiology, Biocenter, University of Würzburg, 97074 Würzburg, Germany.

Abstract: Chlamydiae are obligate intracellular bacterial pathogens that have a major effect on human health. Because of their intimate association with their host, chlamydiae depend on various host cell functions for their survival. Here, we present an RNA-interference–based screen in human epithelial cells that identified 59 host factors that either positively or negatively influenced the replication of Chlamydia trachomatis (Ctr). Two factors, K-Ras and Raf-1, which are members of the canonical Ras–Raf–MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase)–ERK (extracellular signal–regulated kinase) pathway, were identified as central components of signaling networks associated with hits from the screen. Depletion of Ras or Raf in HeLa cells increased pathogen growth. Mechanistic analyses revealed that ERK was activated independently of K-Ras and Raf-1. Infection with Ctr led to the Akt-dependent, increased phosphorylation (and inactivation) of Raf-1 at serine-259. Furthermore, phosphorylated Raf-1 relocalized from the cytoplasm to the intracellular bacterial inclusion in an Akt- and 14-3-3β–dependent manner. Together, these findings not only show that Chlamydia regulates components of an important host cell signaling pathway, but also provide mechanistic insights into how this is achieved.

§ To whom correspondence should be addressed. E-mail: meyer{at}mpiib-berlin.mpg.de

Citation: R. K. Gurumurthy, A. P. Mäurer, N. Machuy, S. Hess, K. P. Pleissner, J. Schuchhardt, T. Rudel, T. F. Meyer, A Loss-of-Function Screen Reveals Ras- and Raf-Independent MEK-ERK Signaling During Chlamydia trachomatis Infection. Sci. Signal. 3, ra21 (2010).

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