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First published online August 3, 2005
doi: 10.1242/10.1242/jcs.02428

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Initiation and termination of NF-B signaling by the intracellular protozoan parasite Toxoplasma gondii

Sagi Shapira¹, Omar S. Harb², Juan Margarit^1,*, Mariana Matrajt^2,*, Jerry Han³, Alexander Hoffmann⁴, Bruce Freedman³, Michael J. May³, David S. Roos² and Christopher A. Hunter^1,

¹ Departments of Pathobiology, University of Pennsylvania, Philadelphia PA 19104, USA
² Departments of Biology, University of Pennsylvania, Philadelphia PA 19104, USA
³ Departments of Animal Biology, University of Pennsylvania, Philadelphia PA 19104, USA
⁴ Department Chemistry and Biochemistry, Signaling Systems Laboratory, University of California at San Diego, La Jolla, CA 92093-0375, USA

Author for correspondence (e-mail: chunter{at}phl.vet.upenn.edu)

Accepted 7 April 2005

Signaling via the NF-B cascade is critical for innate recognition of microbial products and immunity to infection. As a consequence, this pathway represents a strong selective pressure on infectious agents and many parasitic, bacterial and viral pathogens have evolved ways to subvert NF-B signaling to promote their survival. Although the mechanisms utilized by microorganisms to modulate NF-B signaling are diverse, a common theme is targeting of the steps that lead to IB degradation, a major regulatory checkpoint of this pathway. The data presented here demonstrate that infection of mammalian cells with Toxoplasma gondii results in the activation of IKK and degradation of IB. However, despite initiation of these hallmarks of NF-B signaling, neither nuclear accumulation of NF-B nor NF-B-driven gene expression is observed in infected cells. However, this defect was not due to a parasite-mediated block in nuclear import, as general nuclear import and constitutive nuclear-cytoplasmic shuttling of NF-B remain intact in infected cells. Rather, in T. gondii-infected cells, the termination of NF-B signaling is associated with reduced phosphorylation of p65/RelA, an event involved in the ability of NF-B to translocate to the nucleus and bind DNA. Thus, these studies demonstrate for the first time that the phosphorylation of p65/RelA represents an event downstream of IB degradation that may be targeted by pathogens to subvert NF-B signaling.

Key words: Toxoplasma gondii, NF-B, Immune regulation, Innate immunity, Host-pathogen interactions, Intracellular signaling

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