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Udgata, Atul and Qureshi, R. and Mukhopadhyay, Sangita (2016) Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors. The Journal of Immunology, 197 (5). pp. 1776-1787. ISSN 0022-1767

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As pathogen-associated molecular pattern sensors, the TLRs can detect diverse ligands to elicit either proinflammatory or anti-inflammatory responses, but the mechanism that dictates such contrasting immune responses is not well understood. In this work, we demonstrate that proline-proline-glutamic acid (PPE)17 protein of Mycobacterium tuberculosis induces TLR1/2 heterodimerization to elicit proinflammatory-type response, whereas PPE18-induced homodimerization of TLR2 triggers anti-inflammatory type responses. Ligation of TLR1/2 caused an increased recruitment of IL-1R-associated kinase (IRAK)1, MyD88, and protein kinase C (PKC)ε to the downstream TLR-signaling complex that translocated PKCε into the nucleus in an IRAK1-dependent manner. PKCε-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP-1), and induction of TNF-α with concomitant downregulation of p38MAPK. Silencing of TLR1 inhibited PPE17-triggered cytoplasmic export of IRAK3 as well as TNF-α induction, suggesting an important role of TLR1/2 heterodimer in regulating proinflammatory responses via the IRAK3-signaling pathway. In contrast, PPE18-mediated homodimerization of TLR2 caused poorer cytoplasmic export of nuclear IRAK3 and MKP-1 stabilization, resulting in increased p38MAPK activation. Our study hints to a novel mechanism that implicates PKCε-IRAK3-MKP-1 signaling in the regulation of MAPK activity and inflammatory cascades downstream of TLR2 in tuberculosis.

Item Type: Article
Depositing User: Dr P Divakar
Date Deposited: 08 Aug 2016 17:47
Last Modified: 30 Sep 2016 08:48
URI: http://cdfd.sciencecentral.in/id/eprint/741

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