Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Leishmania donovani targets tumor necrosis factor
receptor-associated factor (TRAF) 3 for impairing
TLR4-mediated host response
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| Creator |
Gupta, Purnima
Giri, Jayeeta Srivastav, Supriya Chande, Ajit G. Mukhopadhyaya, Robin Das, Pijush K Ukil, Anindita |
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| Subject |
Infectious Diseases and Immunology
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| Description |
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 receptorassociated
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 ubiquitinatio
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-� (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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| Publisher |
Federation of American Society of Experimental Biology
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| Date |
2014
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2040/1/FASEB_JOURNAL___28__(_4)_1756%2D1768;2014[33].pdf
Gupta, Purnima and Giri, Jayeeta and Srivastav, Supriya and Chande, Ajit G. and Mukhopadhyaya, Robin and Das, Pijush K and Ukil, Anindita (2014) Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response. The FASEB Journal, 28 (4). pp. 1756-1768. ISSN 0892-6638 |
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| Relation |
http://dx.doi.org/10.1096/fj.13-238428
http://www.eprints.iicb.res.in/2040/ |
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