A novel form of NF-kappaB is induced by Leishmania infection: involvement in macrophage gene expression.
Leishmania spp. are obligate intracellular parasites that inhabit the phagolysosomes of macrophages. Manipulation of host cell signaling pathways and gene expression by Leishmania is critical for Leishmania's survival and resultant pathology. Here, we show that infection of macrophages with Leishmania promastigotes in vitro causes specific cleavage of the NF-kappaB p65 RelA subunit. Cleavage occurs in the cytoplasm and is dependent on the Leishmania protease gp63. The resulting fragment, p35 RelA, migrates to the nucleus, where it binds DNA as a heterodimer with NF-kappaB p50. Importantly, induction of chemokine gene expression (MIP-2/CXCL2, MCP-1/CCL2, MIP-1alpha/CCL3, MIP-1beta/CCL4) by Leishmania is NF-kappaB dependent, which implies that p35 RelA/p50 dimers are able to activate transcription, despite the absence of a recognized transcriptional transactivation domain. NF-kappaB cleavage was observed following infection with a range of pathogenic species, including L. donovani, L. major, L. mexicana, and L. (Viannia) braziliensis, but not the non-pathogenic L. tarentolae or treatment with IFN-gamma. These results indicate a novel mechanism by which a pathogen can subvert a macrophage's regulatory pathways to alter NF-kappaB activity.
Gregory
David J
DJ
Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montréal, Canada.
Godbout
Marianne
M
Contreras
Irazú
I
Forget
Geneviève
G
Olivier
Martin
M
D000818:Animals; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology*; D007891:Leishmania / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D018925:Chemokines; D016328:NF-kappa B; D051996:Transcription Factor RelA; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D020169:Caspases; D003546:Cysteine Endopeptidases; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania