title: Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors.
abstract: 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.
authors.affiliation: Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India; and Graduate Studies, Manipal University, Manipal, Karnataka 576 104, India.
authors.forename: Atul
authors.initials: A
authors.lastname: Udgata
authors.affiliation: Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India; and.
authors.forename: Rahila
authors.identifier: 0000-0002-3633-784X
authors.initials: R
authors.lastname: Qureshi
authors.affiliation: Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India; and sangita@cdfd.org.in.
authors.forename: Sangita
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000276:immunology; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C530985:Rv1168c protein, Mycobacterium tuberculosis; C544170:Rv1196 protein, Mycobacterium tuberculosis; C434984:TIRAP protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C507768:IRAK1 protein, human; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051744:Protein Kinase C-epsilon; D020929:Mitogen-Activated Protein Kinase Kinases