Proteasome-mediated Degradation of STAT1α following Infection of Macrophages with Leishmania donovani

Activation of the Janus-activated kinase 2 (JAK2)/STAT1α 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. STAT1α nuclear localization was shown to be rapidly reduced by the infection. Western blot analysis revealed that cellular STAT1α, 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 STAT1α degradation. We further demonstrated that degradation was receptor-mediated and involved protein kinase Cα. All Leishmania species tested (L. major, L. donovani, L. mexicana, L. braziliensis), but not the related parasite Trypanosoma cruzi, caused STAT1α 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. Activation of the Janus-activated kinase 2 (JAK2)/STAT1α 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. STAT1α nuclear localization was shown to be rapidly reduced by the infection. Western blot analysis revealed that cellular STAT1α, 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 STAT1α degradation. We further demonstrated that degradation was receptor-mediated and involved protein kinase Cα. All Leishmania species tested (L. major, L. donovani, L. mexicana, L. braziliensis), but not the related parasite Trypanosoma cruzi, caused STAT1α 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. Intracellular protozoan parasites of the Leishmania genus are the etiological agents of leishmaniasis, a condition that causes considerable worldwide morbidity and mortality, with pathologies ranging from disfiguring cutaneous to lethal visceral afflictions (1Herwaldt B.L. Lancet. 1999; 354: 1191-1199Abstract Full Text Full Text PDF PubMed Scopus (1378) Google Scholar). Survival of these pathogens within the phagocytic cells of the host requires rapid alteration of macrophage signal transduction, resulting in abnormal immune functions (reviewed in Refs. 2Mansfield J.M. Olivier M. Kaufmann S.H.E. Sher A. Ahmed R. Immunology of Infectious Diseases. ASM Press, Washington, D. C.2002: 379-392Google Scholar and 3Olivier M. Gregory D.J. Forget G. Clin. Microbiol. Rev. 2005; 18: 293-305Crossref PubMed Scopus (375) Google Scholar). For instance, macrophage dysfunctions, such as failure to respond to interferon γ (IFNγ), 1The abbreviations used are: IFNγ, interferon γ; CR3, complement receptor 3; EMSA, electrophoretic mobility shift assay; GAS/ISRE, γ-activated sequence/interferon stimulation response element; JAK, Janus-activated kinase; PKC, protein kinase C; PTP, protein tyrosine phosphatase; PIAS-1, protein inhibitor of activated STAT1; SOCS-1, suppressor of cytokine signalling-1; STAT, signal transducer and activator of transcription; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; bpV(phen), potassium bispexoxol(1, 10-phenanthroline) oxovanadate. have been linked to altered signaling cascades, including Ca2+-, PKC (protein kinase C)-, MAPK (mitogen-activated protein kinase)-, and JAK2 (Janus-activated kinase 2)-dependent pathways (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 5Martiny A. Meyer-Fernandes J.R. de Souza W. Vannier-Santos M.A. Mol. Biochem. Parasitol. 1999; 102: 1-12Crossref PubMed Scopus (77) Google Scholar, 6Nandan D. Reiner N.E. Infect. Immun. 1995; 63: 4495-4500Crossref PubMed Google Scholar, 7Nandan D. Lo R. Reiner N.E. Infect. Immun. 1999; 67: 4055-4063Crossref PubMed Google Scholar, 8Olivier M. Baimbridge K.G. Reiner N.E. J. Immunol. 1992; 148: 1188-1196PubMed Google Scholar, 9Olivier M. Brownsey R.W. Reiner N.E. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7481-7485Crossref PubMed Scopus (116) Google Scholar, 10Olivier M. Parasitol. Today. 1996; 12: 145-150Abstract Full Text PDF PubMed Scopus (46) Google Scholar, 11Turco S.J. Parasite Immunol. (Oxf.). 1999; 21: 597-600Crossref PubMed Scopus (21) Google Scholar). Manipulation of these signaling pathways distorts the activities of transcription factors, such as STAT1α, which is important for the expression of IFNγ-induced genes, such as inducible nitric-oxide synthase and major histocompatibility complex class II (12Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Crossref PubMed Scopus (5028) Google Scholar). We have previously shown that the unresponsiveness of the JAK2 signaling pathway in Leishmania donovani-infected macrophages upon IFNγ stimulation was due to the ability of the parasite to activate a particular protein tyrosine phosphatase (PTP), SHP-1 (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar). SHP-1 is a known inhibitor of several tyrosine kinase-dependent pathways, including the JAK2/STAT1α pathway, where it dephosphorylates JAK2 (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 13Klingmuller U. Lorenz U. Cantley L.C. Neel B.G. Lodish H.F. Cell. 1995; 80: 729-738Abstract Full Text PDF PubMed Scopus (842) Google Scholar, 14Knutson K.L. Hmama Z. Herrera-Velit P. Rochford R. Reiner N.E. J. Biol. Chem. 1998; 273: 645-652Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). However, our observation that IFNγ-stimulated STAT1α activity is also reduced in SHP-1-deficient macrophages following L. donovani infection indicates that Leishmania employs further mechanisms to inhibit STAT1 activity. 2G. Forget, D. J. Gregory, and M. Olivier, manuscript submitted. Aside from SHP-1, numerous physiological and pathogen-induced proteins have been shown to regulate JAK/STAT pathways (15Wormald S. Hilton D.J. J. Biol. Chem. 2004; 279: 821-824Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar). Indeed, alternative splicing of the STAT1 mRNA itself produces a dominant negative variant, STAT1β, which binds the same promoter elements as STAT1α but lacks a crucial transcription activation domain (16Bromberg J.F. Horvath C.M. Wen Z. Schreiber R.D. Darnell Jr., J.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7673-7678Crossref PubMed Scopus (444) Google Scholar, 17Zakharova N. Lymar E.S. Yang E. Malik S. Zhang J.J. Roeder R.G. Darnell Jr., J.E. J. Biol. Chem. 2003; 278: 43067-43073Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). The intracellular bacterium Mycobacterium avium appears to induce STAT1β to inhibit macrophage STAT1α activity (18Alvarez G.R. Zwilling B.S. Lafuse W.P. J. Immunol. 2003; 171: 6766-6773Crossref PubMed Scopus (43) Google Scholar). Members of the suppressor of cytokine signaling (SOCS) family of proteins are induced by stimulation with various cytokines and provide negative feedback to the response of the cell to cytokine treatment (19Johnston J.A. J. Leukocyte Biol. 2004; 75: 743-748Crossref PubMed Scopus (51) Google Scholar, 20Kile B.T. Alexander W.S. Cell. Mol. Life Sci. 2001; 58: 1627-1635Crossref PubMed Scopus (144) Google Scholar). SOCS proteins are capable of acting as ubiquitin ligases, and inhibition of signaling by proteasome-mediated receptor degradation has been proposed to contribute to inactivation of various STATs (21Callus B.A. Mathey-Prevot B. Blood. 1998; 91: 3182-3192Crossref PubMed Google Scholar, 22Haspel R.L. Salditt-Georgieff M. Darnell Jr., J.E. EMBO J. 1996; 15: 6262-6268Crossref PubMed Scopus (272) Google Scholar, 23Verdier F. Chretien S. Muller O. Varlet P. Yoshimura A. Gisselbrecht S. Lacombe C. Mayeux P. J. Biol. Chem. 1998; 273: 28185-28190Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 24Verdier F. Walrafen P. Hubert N. Chretien S. Gisselbrecht S. Lacombe C. Mayeux P. J. Biol. Chem. 2000; 275: 18375-18381Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 25Yu C.L. Burakoff S.J. J. Biol. Chem. 1997; 272: 14017-14020Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 26De Sepulveda P. Ilangumaran S. Rottapel R. J. Biol. Chem. 2000; 275: 14005-14008Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 27Frantsve J. Schwaller J. Sternberg D.W. Kutok J. Gilliland D.G. Mol. Cell. Biol. 2001; 21: 3547-3557Crossref PubMed Scopus (143) Google Scholar). Although IFNγ-activated STAT1 has been shown to be ubiquitinated and protein levels have been stabilized by inhibitors of the proteasome, details of this mechanism and whether the SOCS family is involved have not been determined (28Kim T.K. Maniatis T. Science. 1996; 273: 1717-1719Crossref PubMed Scopus (361) Google Scholar). SOCS family members have also been reported to prevent STAT phosphorylation by binding and by for STAT binding M. M. R. A. S. M. T. N. T. T. S. Yoshimura A. 1997; PubMed Scopus Google Scholar, A. M. M. M. A. Yoshimura A. Blood. 1997; 89: PubMed Google Scholar, A. T. T. D.J. T. A. EMBO J. 1995; PubMed Scopus Google Scholar). have a of mechanisms for IFNγ including of and dominant negative B. T. J. Rev. 12: PubMed Scopus Google Scholar). particular proteins have been shown to degradation of STAT1 by the proteasome by a cellular D. F. S. D. J. 2004; PubMed Scopus Google Scholar, L. S. J. 1999; PubMed Google Scholar, C.M. Horvath C.M. PubMed Scopus Google Scholar). However, have reported that this degradation is and that inhibition of STAT1 phosphorylation is a important mechanism B. T. J. Rev. 12: PubMed Scopus Google Scholar, T. J. B. J. 2000; PubMed Scopus Google Scholar). our microbial has been reported to STAT1α by proteasome-mediated degradation. In the present study, we the mechanisms Leishmania infection causes macrophage STAT1α inactivation. results that abnormal STAT1α nuclear translocation in Leishmania-infected macrophages be the of rapid and STAT1α protein and that this contribute to the of response to The was shown to be to STAT1α, as levels and was by the the and host study further protein kinase signaling and not in this these results for a of the proteasome pathway in the of STAT1α in macrophages by the protozoan parasite a new mechanism microbial pathogens microbicidal activity. donovani and Leishmania major Leishmania mexicana, and Leishmania Trypanosoma and immortalized bone marrow-derived cell and G. Siminovitch K.A. S. S. D. Olivier M. Eur. J. Immunol. 2001; PubMed Scopus Google as previously S.J. J. Immunol. PubMed Scopus Google Scholar, D. T. M. L. L. E. J. Leukocyte Biol. PubMed Scopus (72) Google Scholar, M. C. J. Faure R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). The was a from 1994; PubMed Scopus Google Scholar). inhibitors used by cells infection. to and from and receptor A. J. J. Immunol. Google was a from The cells for to for 2 the of IFNγ and Western as previously M. M. Olivier M. J. Immunol. 2005; PubMed Scopus Google Scholar). The for was and a from and from from and from and All are of in with and with of for The with of and with of in for in a and with for the the and an cells and in of and inhibitor with of and for a with and the in of for was the to by and by of L. donovani STAT1α have reported that signaling is altered in Leishmania-infected macrophages (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 6Nandan D. Reiner N.E. Infect. Immun. 1995; 63: 4495-4500Crossref PubMed Google Scholar). Although JAK2 phosphorylation was shown to be the STAT1α activity has not been We whether STAT1 activation by IFNγ stimulation was in Leishmania-infected macrophages. shown in to nuclear STAT1 binding activity in response to However, this was in Leishmania-infected macrophages. the STAT1 nuclear signal in macrophages was in cells in to was important to the in which this STAT1 in STAT1 nuclear signal rapidly in L. donovani-infected cells in the absence of IFNγ, and was This with IFNγ treatment of which in a in STAT1 nuclear levels of STAT1 infection from its in the for due to a failure to tyrosine also a in cellular STAT1 these we STAT1α protein as as its phosphorylation in cell with the EMSA, we that Leishmania IFNγ not to STAT1α phosphorylation we that STAT1α protein levels rapidly in the of Leishmania and in by the of infection. This observation to that STAT1α degradation is responsible for the absence of STAT1 from the it that this was to STAT1α, protein was by L. donovani infection. of STAT1α from the nucleus was further by observation with Leishmania with IFNγ for STAT1α for STAT1α protein in macrophages IFNγ stimulation to of STAT1α in the nucleus in Leishmania-infected macrophages a was revealed in that nuclear STAT1α was with localization in the that STAT1α degradation in the and SHP-1 in STAT1α have reported evidence for a for in STAT1 regulation (21Callus B.A. Mathey-Prevot B. Blood. 1998; 91: 3182-3192Crossref PubMed Google Scholar, 22Haspel R.L. Salditt-Georgieff M. Darnell Jr., J.E. EMBO J. 1996; 15: 6262-6268Crossref PubMed Scopus (272) Google Scholar, 25Yu C.L. Burakoff S.J. J. Biol. Chem. 1997; 272: 14017-14020Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, R.L. Darnell Jr., J.E. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). we have previously Leishmania infection to PTP and SHP-1 activation (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, G. Siminovitch K.A. S. S. D. Olivier M. Eur. J. Immunol. 2001; PubMed Scopus Google Scholar, M. C. J. Faure R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). was to whether the STAT1α inactivation was upon these shown in our results demonstrated that inhibition of by not prevent the rapid of STAT1 by Leishmania infection. In we further demonstrated that the PTP SHP-1 is not involved in STAT1α inactivation by immortalized macrophages from with G. Siminovitch K.A. S. S. D. Olivier M. Eur. J. Immunol. 2001; PubMed Scopus Google Scholar). in the of STAT1 nuclear degradation was and SHP-1-deficient for the translocation in Indeed, the STAT1 signal was in the absence of SHP-1. This is with the that SHP-1 is known to regulate JAK2 phosphorylation U. Lorenz U. Cantley L.C. Neel B.G. Lodish H.F. Cell. 1995; 80: 729-738Abstract Full Text PDF PubMed Scopus (842) Google Scholar). in its JAK2 activity STAT1 nuclear STAT1α the STAT1α proteins Leishmania we the of in this with of and a proteasome infection with in in STAT1 in the nucleus and these inhibitors also restored STAT1α protein in cell infection results to in the of Leishmania STAT1α is the of Leishmania and in STAT1α present study has demonstrated that infection of macrophages with L. donovani causes STAT1α inactivation by degradation. was important to whether Leishmania species protozoan pathogens the same in and tested Leishmania species (L. donovani, L. major, L. mexicana, and L. caused STAT1α degradation. However, T. cruzi, a protozoan of the same family as of the by macrophages the of Leishmania species with the macrophages STAT1α degradation and be to of The degradation that we as as parasite an for parasite We whether macrophage previously in a to in STAT1α inactivation. of STAT1α be by receptor such as the complement receptor the receptor for the of γ and the receptor are known to Leishmania J. Immunol. Google Scholar, A. J. PubMed Scopus Google Scholar, Biol. PubMed Scopus Google Scholar). Using these we to Leishmania and the STAT1 nuclear that a to in STAT1 inactivation the translocation of STAT1 was restored the of the receptor was The parasite that to these are the and the Biol. PubMed Scopus Google Scholar). We whether be in STAT1α inactivation by Leishmania parasites for to STAT1 nuclear translocation not However, we the of and The in STAT1α results showed that of macrophage has a to in STAT1α we whether signaling was induced following receptor that is activated by and binding is the protein kinase M.A. J. Immunol. Google Scholar). a linked to activation of pathways to degradation R.L. 1999; PubMed Scopus Google Scholar). We whether Leishmania infection activated by its in Leishmania and macrophages for as as phosphorylation of which was for infection. whether activation in Leishmania-infected cells induced STAT1α degradation by the proteasome, we macrophages with of a PKC inhibitor for in inhibition of significantly restored STAT1 nuclear translocation in macrophages. signaling to to STAT1α to the proteasome in Leishmania-infected macrophages. of STAT1α to the Leishmania which to STAT1α and it to the proteasome pathway, we used a of STAT1α that and cells Indeed, proteins Leishmania showed phosphorylation we that proteins This is with the that STAT1α is by this not Leishmania is known for its ability to numerous macrophage functions that are to its survival and M. Gregory D.J. Forget G. Clin. Microbiol. Rev. 2005; 18: 293-305Crossref PubMed Scopus (375) Google Scholar, 10Olivier M. Parasitol. Today. 1996; 12: 145-150Abstract Full Text PDF PubMed Scopus (46) Google Scholar, L. R. S. Muller W. R. J. 1996; PubMed Scopus Google Scholar, N. Reiner N.E. Infect. Immun. 1992; PubMed Google Scholar, L. M.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus (155) Google Scholar). of these are induced by cytokines such as IFNγ major histocompatibility the parasite has to inhibit the signaling pathways activated by such the JAK2/STAT1α and protein kinase pathways (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 5Martiny A. Meyer-Fernandes J.R. de Souza W. Vannier-Santos M.A. Mol. Biochem. Parasitol. 1999; 102: 1-12Crossref PubMed Scopus (77) Google Scholar, 6Nandan D. Reiner N.E. Infect. Immun. 1995; 63: 4495-4500Crossref PubMed Google Scholar, 7Nandan D. Lo R. Reiner N.E. Infect. Immun. 1999; 67: 4055-4063Crossref PubMed Google Scholar). (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 7Nandan D. Lo R. Reiner N.E. Infect. Immun. 1999; 67: 4055-4063Crossref PubMed Google have demonstrated that the inhibition of JAK2 and infection was by the PTP SHP-1. 2G. Forget, D. J. Gregory, and M. Olivier, manuscript submitted. The of the present study was to mechanisms that responsible for this inactivation. We that the STAT1 nuclear translocation and STAT1α protein in a in Leishmania-infected macrophages. This following infection with and species of L. donovani, major, mexicana, and for a the The that we of STAT1α following of the infection with a indicates that the is to Leishmania infection and is not a of cell have inhibition of STATs by various to the of a PTP proteins (21Callus B.A. Mathey-Prevot B. Blood. 1998; 91: 3182-3192Crossref PubMed Google Scholar, 22Haspel R.L. Salditt-Georgieff M. Darnell Jr., J.E. EMBO J. 1996; 15: 6262-6268Crossref PubMed Scopus (272) Google Scholar, 25Yu C.L. Burakoff S.J. J. Biol. Chem. 1997; 272: 14017-14020Abstract Full Text Full Text PDF PubMed Scopus (105) Google a nuclear PTP STAT1 R.L. Darnell Jr., J.E. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). This is further by a study a nuclear localization in the SHP-1 W. M. T. Mol. PubMed Scopus (21) Google Scholar). the present study, immortalized macrophages from PTP SHP-1-deficient and G. Siminovitch K.A. S. S. D. Olivier M. Eur. J. Immunol. 2001; PubMed Scopus Google and the PTP inhibitor Faure R. D. G. B.S. J. Biol. Chem. 1994; Full Text PDF PubMed Google we that SHP-1 are responsible for the of STAT1 from the of Leishmania-infected as the activation of STAT1α following cytokine stimulation is by the protein inhibitor of activated STAT1 This binds STAT1α and its B. J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google by D. S. N. Yang J. S. J.J. O. Blood. 2003; 102: PubMed Scopus Google Scholar, Horvath C.M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). We its by whether Leishmania infection promote its to we have been to and STAT1α from macrophages not which indicates that the we was independent of we that the inhibition is due to the STAT1α protein was with in cell of macrophages and was Using we to that STAT1α in the Members of the SOCS have been shown to STAT1α by binding and such as by a ubiquitin to proteasome-mediated degradation (15Wormald S. Hilton D.J. J. Biol. Chem. 2004; 279: 821-824Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, J.A. J. Leukocyte Biol. 2004; 75: 743-748Crossref PubMed Scopus (51) Google Scholar). that Leishmania infection expression of which binds to STAT1α, resulting in its and degradation. However, a of with this SOCS proteins and STAT1α has been appears to by is known to induce degradation of JAK2 (19Johnston J.A. J. Leukocyte Biol. 2004; 75: 743-748Crossref PubMed Scopus (51) Google Scholar, 20Kile B.T. Alexander W.S. Cell. Mol. Life Sci. 2001; 58: 1627-1635Crossref PubMed Scopus (144) Google but the JAK2 protein following infection (4Blanchette J. Racette N. Faure R. Siminovitch K.A. Olivier M. Eur. J. Immunol. 1999; 29: 3737-3744Crossref PubMed Scopus (140) Google Scholar, 6Nandan D. Reiner N.E. Infect. Immun. 1995; 63: 4495-4500Crossref PubMed Google Scholar). we have been to expression in cells by blot not family has been shown to be induced by L. donovani in macrophages S. F. Infect. Immun. 2003; PubMed Scopus Google Scholar). However, from that STAT1α by mechanisms its R. E. J. R. Immunol. 2003; PubMed Scopus Google Scholar, B.A. Zhang S. L. D. Hilton D.J. Alexander W.S. Immunol. 2003; PubMed Scopus Google Scholar). these that Leishmania-induced degradation of STAT1α is to be by SOCS have proteasome-mediated degradation of STATs following cytokine study showed following phosphorylation in response to IFNγ, STAT1α is ubiquitinated and (28Kim T.K. Maniatis T. Science. 1996; 273: 1717-1719Crossref PubMed Scopus (361) Google Scholar). study showed that was stimulation R.L. 1999; PubMed Scopus Google Scholar). In the STAT was by inhibition of the We that the of proteasome and the rescued STAT1α nuclear translocation as as restored its protein in Leishmania-infected macrophages. We that Leishmania infection results in proteasome-mediated degradation of This with the mechanisms of of STAT1α following cytokine where activity is reduced but is not (15Wormald S. Hilton D.J. J. Biol. Chem. 2004; 279: 821-824Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, B.A. Mathey-Prevot B. Blood. 1998; 91: 3182-3192Crossref PubMed Google Scholar, 22Haspel R.L. Salditt-Georgieff M. Darnell Jr., J.E. EMBO J. 1996; 15: 6262-6268Crossref PubMed Scopus (272) Google Scholar, 23Verdier F. Chretien S. Muller O. Varlet P. Yoshimura A. Gisselbrecht S. Lacombe C. Mayeux P. J. Biol. Chem. 1998; 273: 28185-28190Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 24Verdier F. Walrafen P. Hubert N. Chretien S. Gisselbrecht S. Lacombe C. Mayeux P. J. Biol. Chem. 2000; 275: 18375-18381Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 25Yu C.L. Burakoff S.J. J. Biol. Chem. 1997; 272: 14017-14020Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). it is of the of various which and degradation of STAT1 by the proteasome D. F. S. D. J. 2004; PubMed Scopus Google Scholar, L. S. J. 1999; PubMed Google Scholar, C.M. Horvath C.M. PubMed Scopus Google Scholar). However, these proteins are within the cell where are to a cellular ubiquitin complex by C.M. Horvath C.M. PubMed Scopus Google Scholar). The of degradation that it is to be caused by a parasite protein to the the Leishmania macrophage to intracellular signaling to STAT1α for degradation. known to to parasite CR3, and the receptor J. Immunol. Google Scholar, A. J. PubMed Scopus Google Scholar, Biol. PubMed Scopus Google Scholar). from receptor demonstrated that contribute to the of STAT1α in the Indeed, STAT1α nuclear translocation was restored in Leishmania-infected cells receptor was was following receptor for this be that Leishmania to to receptor a for and this it has been demonstrated that Leishmania to for to A. G. B.S. Infect. Immun. 1999; 67: PubMed Google Scholar). for the of these are known to Leishmania and (reviewed in C. M. J. Parasitol. 1998; PubMed Scopus Google Scholar). For this we the of these in STAT1α inactivation by parasite The absence of not STAT1α nuclear translocation not However, this not in this and to and be In the absence of we not this and to PKC activation M.A. J. Immunol. Google Scholar). this kinase be important in STAT1α inactivation. showed that was activated in macrophages from to following infection. This is with the of STAT1α Using a PKC inhibitor we to in our STAT1α nuclear inactivation. This is in with a degradation by the proteasome R.L. 1999; PubMed Scopus Google Scholar). analysis of STAT1α by to of proteins with STAT1α in macrophages and macrophages with Leishmania for This is a that Leishmania infection protein complex in and the is of in the phosphorylation of a of of these to the mechanisms STAT1α degradation by the this study has a mechanism by Leishmania to macrophage STAT1α degradation by the proteasome in the of infection. This to by the of macrophage and the by the parasite and the degradation of STAT1α, in to the inhibition of JAK2 by SHP-1, the parasite is to inhibit the response of the host cell to This favors its within the cell and propagation of the We are to for the and for the bpV(phen), and for the receptor

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