A novel form of NF‐κB is induced by Leishmania infection: Involvement in macrophage gene expression

Abstract

2Leishmania 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-jB p65RelA subunit. Cleavage occurs in the cytoplasm and is dependent on the Leishmania protease gp63. The resulting fragment, p35RelA , migrates to the nucleus, where it binds DNA as a heterodimer with NF-jB p50. Importantly, induction of chemokine gene expression (MIP-2/CXCL2, MCP-1/CCL2, MIP-1a/CCL3, MIP-1b/CCL4) by Leishmania is NF-jB dependent, which implies that p35 RelA /p50 dimers are able to activate transcription, despite the absence of a recognized transcriptional transactivation domain. NF-jB 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-c. These results indicate a novel mechanism by which a pathogen can subvert a macrophage's regulatory pathways to alter NF-jB activity.

Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

“…Taken together, these data indicate that although some sensitisers activate the NF-kB transcription factor and are probably responsible for some phenotypic modifications observed in DC, other sensitisers failed to activate this signalling pathway. For the group of sensitising chemicals that were unsuccessful in activating NF-kB, we can speculate that the phenotypical modifications observed are probably controlled by other signalling pathways and transcription factors, such as MAPKs and NRF2, or alternatively, a non-canonical pathway of NF-kB activation could be induced by allergens, as previously reported with other dendritic cell antigens (Gregory et al, 2008).…”

GTPase Sar1 regulates the trafficking and secretion of the virulence factor gp63 in Leishmania

“…Moreover, Ldgp63 is shown to modulate the critical serine/threonine kinases to hijack host macrophage signalling for their survival in macrophages (12). Ldgp63 also degrades several transcription factors like NF-kB, STAT1 and AP-1 to alter gene expression in macrophages (13)(14)(15). Interestingly, Ldgp63 is found to manipulate the translational system of host cell by cleaving mTOR (16).…”

Leishmania, the phagosome, and host responses: The journey of a parasite

“…GP63 also selectively downregulates host cell protein synthesis through alterations of the mTORC1-dependent signaling [56]. GP63 inactivates various transcription factors such as AP-1 and NF-B through specific cleavage and degradation of different subunits [57,58]. More recently, GP63 was shown to target the nuclear envelop, where it degrades nucleoporins of the nuclear pore complexes [59].…”