title: Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling.
abstract: Glutaredoxin-1 (GRX-1) is a cytoplasmic enzyme that highly contributes to the antioxidant defense system. It catalyzes the reversible reduction of glutathione-protein mixed disulfides, a process called deglutathionylation. Here, we investigated the role of GRX-1 in the pathway triggered by interleukin-1/Toll-like receptor 4 (IL-1R/TLR4) by using RNA interference (RNAi) in HEK293 and HeLa cells. TNF receptor-associated factor 6 (TRAF6) is an intermediate signalling molecule involved in the signal transduction by members of the interleukin-1/Toll-like receptor (IL-1R/TLR) family. TRAF6 has an E3 ubiquitin ligase activity which depends on the integrity of an amino-terminal really interesting new gene (RING) finger motif. Upon receptor activation, TRAF6 undergoes K63-linked auto-polyubiquitination which mediates protein-protein interactions and signal propagation. Our data showed that IL-1R and TLR4-mediated NF-κB induction was severely reduced in GRX-1 knockdown cells. We found that the RING-finger motif of TRAF6 is S-glutathionylated under normal conditions. Moreover, upon IL-1 stimulation TRAF6 undergoes deglutathionylation catalyzed by GRX-1. The deglutathionylation of TRAF6 is essential for its auto-polyubiquitination and subsequent activation. Taken together, our findings reveal another signalling molecule affected by S-glutathionylation and uncover a crucial role for GRX-1 in the TRAF6-dependent activation of NF-κB by IL-1R/TLRs.
authors.affiliation: Center of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, 4 Soranou Efesiou Street, Athens 11527, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Chantzoura
authors.forename: Efthimios
authors.initials: E
authors.lastname: Prinarakis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Panagopoulos
authors.forename: George
authors.initials: G
authors.lastname: Mosialos
authors.forename: Giannis
authors.initials: G
authors.lastname: Spyrou
mesh_terms: D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D054829:RING Finger Domains; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D054477:Glutaredoxins; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D005978:Glutathione