title: 14-3-3ε and 14-3-3σ inhibit Toll-like receptor (TLR)-mediated proinflammatory cytokine induction.
abstract: Toll-like receptors (TLRs) are a group of pattern recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Limited studies have applied proteomics toward understanding the dynamics of TLR signaling. Herein, a proteomics approach identified 14-3-3ε and 14-3-3σ proteins as new members of the TLR signaling complex. Toward the functional characterization of 14-3-3ε and 14-3-3σ in TLR signaling, we have shown that both of these proteins impair TLR2, TLR3, TLR4, TLR7/8, and TLR9 ligand-induced IL-6, TNFα, and IFN-β production. We also show that 14-3-3ε and 14-3-3σ impair TLR2-, TLR3-, TLR4-, TLR7/8-, and TLR9-mediated NF-κB and IFN-β reporter gene activity. Interestingly, although the 14-3-3 proteins inhibit poly(I:C)-mediated RANTES production, 14-3-3 proteins augment Pam(3)CSK(4), LPS, R848, and CpG-mediated production of RANTES (regulated on activation normal T cell expressed and secreted) in a Mal (MyD88 adaptor-like)/MyD88-dependent manner. 14-3-3ε and 14-3-3σ also bind to the TLR adaptors and to both TRAF3 and TRAF6. Our study conclusively shows that 14-3-3ε and 14-3-3σ play a major regulatory role in balancing the host inflammatory response to viral and bacterial infections through modulation of the TLR signaling pathway. Thus, manipulation of 14-3-3 proteins may represent novel therapeutic targets for inflammatory conditions and infections.
authors.affiliation: Immune Signaling Group, Institute of Immunology, Department of Biology, National University of Ireland Maynooth, County Kildare, Ireland.
authors.forename: Aisha Qasim
authors.initials: AQ
authors.lastname: Butt
authors.forename: Suaad
authors.initials: S
authors.lastname: Ahmed
authors.forename: Ashwini
authors.initials: A
authors.lastname: Maratha
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Miggin
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011070:Poly I-C / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D016207:Cytokines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D011070:Poly I-C