Role of Gold in Inflammation and Tristetraprolin Activity

The zinc finger protein tristetraprolin (TTP) regulates inflammation by downregulating cytokine mRNAs. Misregulation results in arthritis, sepsis and cancer, and there is an interest in modulating TTP activity with exogenous agents. Gold has anti‐inflammatory properties and has recently been shown to modulate the signaling pathway that produces TTP, suggesting that TTP may be a target of gold. The reactivity of [AuIII(terpy)Cl]Cl2 with TTP was investigated by UV/Vis spectroscopy, spin‐filter inductively coupled plasma mass spectrometry, X‐ray absorption spectroscopy and native electrospray ionization mass spectrometry. AuIII was found to replace zinc in the protein active site in the reduced AuI form, with the AuI ion coordinated to two cysteine residues in a linear geometry. The replacement of ZnII with AuI results in loss of both secondary structure and RNA binding function. In contrast, when ZnIITTP is bound to its RNA target, no replacement of ZnII with AuI is observed, even in the presence of excess AuIIIterpy. This discovery of differential reactivity of gold with TTP versus TTP/RNA offers a potential strategy for selective targeting with gold complexes to control inflammation. Silentium est aureum (silence is golden): AuIIIterpy silences the activity of the zinc finger protein tristetraprolin (TTP), a key arbiter of inflammation. Conversely, when TTP is bound to RNA, the RNA protects the TTP zinc finger site from gold silencing, offering a new approach for selective modulation of zinc finger protein activity.