Journal
FASEB JOURNAL
Volume 28, Issue 4, Pages 1756-1768Publisher
WILEY
DOI: 10.1096/fj.13-238428
Keywords
signalosome; ubiquitination; macrophage
Categories
Funding
- Department of Science and Technology (DST)
- University Grants Commission (UGC)
- Department of Biotechnology (DBT)
- Council of Scientific and Industrial Research (CSIR), Government of India
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Intramacrophage pathogen Leishmania donovani escapes host immune response by subverting Toll-like receptor (TLR) signaling, which is critically regulated by protein ubiquitination. In the present study, we identified tumor necrosis factor receptor-associated factor (TRAF) 3, degradative ubiquitination of which is essential for TLR4 activation, as a target for Leishmania to deactivate LPS-mediated TLR4 signaling. We used LPS-treated RAW 264.7 cells and compared the TLR4-mediated immune response in these cells with L. donovani and L. donovani + LPS costimulated macrophages. TRAF3, which was ubiquitinated (2.1-fold over control) at lys 48 position and subsequently degraded following LPS treatment, persisted in L. donovani and L. donovani + LPS costimulated cells due to defective lys 48 ubiquitination. Lys 63-linked ubiquitination of upstream proteins in the cascade (cIAP1/2 and TRAF6), mandatory for TRAF3 degradation, was also reduced postinfection. This may be attributed to reduced association between ubiquitin-conjugating enzyme Ubc13 and TRAF6 during infection. Inhibition of TRAF3 before infection by shRNA in Balb/c mice showed enhanced IL-12 and TNF-alpha (10.8- and 8.1-fold over infected control) and decreased spleen parasite burden (61.3% suppression, P < 0.001), thereby marking reduction in disease progression. Our findings identified TRAF3 as a novel molecular regulator exploited by Leishmania for successful infection.-Gupta, P., Giri, J., Srivastav, S., Chande, A. G., Mukhopadhyaya, R., Das, P. K., Ukil, A. Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response.
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