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J. Biol. Chem., Vol. 280, Issue 34, 30542-30549, August 26, 2005

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Proteasome-mediated Degradation of STAT1 following Infection of Macrophages with Leishmania donovani^*

Geneviève Forget, David J. Gregory¶, and Martin Olivier¶||**

From the Centre de Recherche en Infectiologie and Département de Biologie Médicale, Centre Hospitalier Universitaire de Québec, Université Laval, Québec G1V 4G2, Canada, ^¶Department of Microbiology and Immunology and Centre for the Study of Host Resistance, Research Institute of McGill University Health Centre, and ^||Division of Experimental Medicine, McGill University, Montreal, Québec H3A 2B4, Canada

Activation of the Janus-activated kinase 2 (JAK2)/STAT1 signaling pathway is repressed in Leishmania-infected macrophages. This represents an important mechanism by which this parasite subverts the microbicidal functions of the cell to promote its own survival and propagation. We recently provided evidence that the protein tyrosine phosphatase (PTP) SHP-1 was responsible for JAK2 inactivation. However, STAT1 translocation to the nucleus was not restored in the absence of SHP-1. In the present study, we have used B10R macrophages to study the mechanism by which this Leishmania-induced STAT1 inactivation occurs. STAT1 nuclear localization was shown to be rapidly reduced by the infection. Western blot analysis revealed that cellular STAT1, but not STAT3, was degraded. Using PTP inhibitors and an immortalized bone marrow-derived macrophage cell line from SHP-1-deficient mice, we showed that STAT1 inactivation was independent of PTP activity. However, inhibition of macrophage proteasome activity significantly rescued Leishmania-induced STAT1 degradation. We further demonstrated that degradation was receptor-mediated and involved protein kinase C. All Leishmania species tested (L. major, L. donovani, L. mexicana, L. braziliensis), but not the related parasite Trypanosoma cruzi, caused STAT1 degradation. Collectively, results from this study revealed a new mechanism for STAT1 regulation by a microbial pathogen, which favors its establishment and propagation within the host.

Received for publication, December 15, 2004 , and in revised form, June 2, 2005.

^* This work was supported by grants from the Canadian Institutes in Health Research (CIHR) (to M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a CIHR Ph.D. studentship.

^** Recipient of a Fonds de la Recherche en Santé du Québec Senior Scholarship, a Burroughs Wellcome Fund Awardee in Molecular Parasitology, and a member of a CIHR Group in host-pathogen interactions. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, McGill University, 3775 University St., Montreal, Québec, H3A 2B4, Canada. Tel.: 514-398-5592; Fax: 514-398-7052; E-mail: martin.olivier{at}mcgill.ca.

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