Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling

Chantzoura, EleniCenter of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece (författare)

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.

Prinarakis, EfthimiosCenter of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece (författare)
Panagopoulos, DimitrisSchool of Biology, Aristotle University of Thessaloniki, Greece (författare)
Mosialos, GeorgeSchool of Biology, Aristotle University of Thessaloniki, Greece (författare)
Spyrou, GiannisCenter of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, Greece(Swepub:liu)ioasp42 (författare)
Center of Basic Research I, Biochemistry Division, Biomedical Research Foundation, Academy of Athens, GreeceSchool of Biology, Aristotle University of Thessaloniki, Greece (creator_code:org_t)

Ingår i:Biochemical and Biophysical Research Communications - BBRC: Elsevier403:3-4, s. 335-3390006-291X1090-2104

Av författaren/redakt...: Chantzoura, Elen ...; Prinarakis, Efth ...; Panagopoulos, Di ...; Mosialos, George; Spyrou, Giannis

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