Leishmania donovanitargets tumor necrosis factor receptor‐associated factor (TRAF) 3 for impairing TLR4‐mediated host response

• DOI: 10.1096/fj.13-238428
• Publication Date: 2014-01-04T01:20:17Z
• Authors: Purnima Gupta; Jayeeta Giri; Supriya Srivastav; Ajit G. Chande; Robin Mukhopadhyaya; Pijush K. Das; Anindita Ukil
• Keywords: Lipopolysaccharides; 0301 basic medicine; Mice, Inbred BALB C; TNF Receptor-Associated Factor 3; Reverse Transcriptase Polymerase Chain Reaction; Lysine; Macrophages; Immunoblotting; Models, Immunological; NF-kappa B; Gene Expression; Interleukin-12; Cell Line; Host-Parasite Interactions; 3. Good health; Mice; 03 medical and health sciences; Animals; Leishmaniasis, Visceral; RNA Interference; Cells, Cultured; Leishmania donovani; Signal Transduction

Intramacrophage pathogen Leishmania donovani escapes host immune response by subverting Toll-like receptor (TLR) signaling, which is critically regulated protein ubiquitination. In the present study, we identified tumor necrosis factor receptor-associated (TRAF) 3, degradative ubiquitination of essential for TLR4 activation, as a target to deactivate LPS-mediated signaling. We used LPS-treated RAW 264.7 cells and compared TLR4-mediated in these with L. + LPS costimulated macrophages. TRAF3, was ubiquitinated (2.1-fold over control) at lys 48 position subsequently degraded following treatment, persisted due defective Lys 63-linked upstream proteins cascade (cIAP1/2 TRAF6), mandatory TRAF3 degradation, also reduced postinfection. This may be attributed association between ubiquitin-conjugating enzyme Ubc13 TRAF6 during infection. Inhibition before infection shRNA Balb/c mice showed enhanced IL-12 TNF-α (10.8- 8.1-fold infected decreased spleen parasite burden (61.3% suppression, P<0.001), thereby marking reduction disease progression. Our findings novel molecular regulator exploited successful infection.—Gupta, P., Giri, J., Srivastav, S., Chande, A. G., Mukhopadhyaya, R., Das, P. K., Ukil, targets 3 impairing response. FASEB J. 28, 28–1756 (1768). www.fasebj.org