The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

Abstract

Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

“…Newly synthesized ZFP36 is rapidly phosphorylated by MAPKAPK2 to promote protection from proteolytic degradation and reduce, or prevent, ARE-dependent destabilizing activity (60). Thus, in LPS-treated Dusp Ϫ/Ϫ mice, there was enhanced MAPK activation and increased inflammatory gene expression despite elevated ZFP36 expression (66).…”

“…Therefore, although glucocorticoids inhibit MAPK activity and reduce inflammation-induced ZFP36, the presence of active GR at the ZFP36 gene locus may act to counteract this by helping to maintain ZFP36 expression. Furthermore, in the presence of pro-inflammatory stimulus plus glucocorticoid, the glucocorticoid-mediated loss of p38 MAPK activity may result in elevated levels of unphosphorylated ZFP36 that displays the greatest ARE-destabilizing activity (60). Indeed, although this effect is described in airway smooth muscle cells (71), a detailed analysis is required to confirm functionality.…”

“…Thus, ZFP36 was present in the phosphorylated form where destabilization activity is low and ARE-containing mRNA translation may actively occur (67). Although a switch to unphosphorylated, and therefore mRNA degradation-active, ZFP36 is driven by the serine/threonine protein phosphatase, PP2A (68,69), this appears to occur later after stimulation, when p38 activity is reduced (60,67). This delay in ZFP36 activation, combined with increased total ZFP36, may therefore explain the enhanced loss of ARE-containing transcripts that occurred at longer IL1B-treatment times after DUSP1 silencing in A549 cells (31,60,63).…”

“…ZFP36 induction occurs in many cells, including A549 epithelial and primary human airway smooth muscle cells (61,62). This requires p38 MAPK to constitute an incoherent feedforward loop with ZFP36 as a negative regulator of ARE-containing mRNAs, such as TNF (60,63) (Fig. 2C, panel i).…”

“…Although many RNAbinding proteins exist and modulate mRNA stability and/or translation, the zinc finger protein, ZFP36, also known as tristetraprolin, is rapidly induced by pro-inflammatory stimuli and is critical for stimulus-dependent down-regulation of AREcontaining mRNAs (60). ZFP36 induction occurs in many cells, including A549 epithelial and primary human airway smooth muscle cells (61,62).…”