TTP (tristetraprolin) is an RNA-binding protein that suppresses inflammation by accelerating the degradation of cytokine mRNAs. TTP binds to an AU-rich element in the 3′-untranslated region of its target mRNAs. In macrophages, the induction of cytokine expression requires activation of the p38-MAPK (mitogen-activated protein kinase)–MK2 [MAPKAP (MAPK-activated protein) kinase-2] kinase cascade. MK2 directly phosphorylates TTP and thereby contributes to transient stabilization of cytokine mRNAs. In the present review, we address the target specificity of TTP, summarize TTP-interacting proteins and discuss how phosphorylation regulates the activity, localization and stability of TTP.

TTP (tristetraprolin) targets cytokine mRNAs for decay

The role of TTP was uncovered by the careful analysis of TTP-knockout mice, which develop generalized inflammation characterized by cachexia, spontaneous arthritis, dermatitis and neutrophilia [1]. The symptoms in these mice are mainly due to overproduction of the pro-inflammatory cytokine TNFα (tumour necrosis factor α). Whereas transcription of the TNFα gene is not affected, macrophages derived from TTP−/− mice exhibit a prolonged TNFα mRNA half-life [2]. In wt (wild-type) macrophages, TTP specifically binds to an ARE (AU-rich element) in the 3′-UTR (3′-untranslated region) of the TNFα mRNA. TTP recognizes the ARE via two cysteine-cysteine-cysteine-histidine zinc-finger domains and causes rapid degradation of its target mRNA. The TTP family of proteins contains two additional paralogues, BRFs (butyrate response factors) 1 and 2, which also promote AMD (ARE-mediated mRNA decay) [3,4].

The ARE was identified as an mRNA-destabilizing element more than 20 years ago [5]. Subsequently, different ARE subclasses were distinguished according to sequence motifs and deadenylation kinetics [6]. Database analysis has suggested that AREs may occur in up to 5% of all mRNAs [7], but functional studies are still lacking that would confirm this estimate. Except for a few well-studied examples, the ARE remains a rather loosely defined entity, and predictions using consensus sequences are not very powerful. A global analysis of mRNA decay rates found that only 10–15% of all mRNAs containing typical ARE motifs have a half-life below 2 h [8]. The heterogeneous nature of AREs is also illustrated by the potential for 15–20 different proteins to bind to and regulate the stability and translation rate of ARE-containing mRNAs [9,10].

Studies addressing target specificity clearly show that TTP binds only to a subset of AREs. In addition to TNFα, bona fide targets of TTP (i.e. targets that have been verified in cells from TTP−/− mice) include the mRNAs encoding GM-CSF (granulocyte/macrophage colony-stimulating factor), IL (interleukin)-2 and Ier3 (immediate early response 3) [1113]. A number of other targets were suggested by knockdown and overexpression studies. A recent genome-wide analysis identified 250 mRNAs that are stabilized in TTP−/− MEFs (mouse embryonic fibroblasts), suggesting that TTP may indeed control a broader set of mRNAs [13]. Our own efforts to identify TTP targets in macrophages using RNA-IP (immunoprecipitation) analysis indicated that TTP associates with more than 100 mRNAs [14]. The 3′-UTRs of these mRNAs are highly enriched in typical ARE motifs, confirming their important role in TTP binding. We demonstrated that, among the newly identified targets, IL-10 mRNA is specifically regulated by TTP. Interestingly, we also found TTP-associated mRNAs that are not elevated in TTP−/− macrophages. Our interpretation is that most transcripts are likely to associate with multiple RNA-binding proteins and that TTP, as part of the mRNP (messenger ribonucleoprotein) complex, may not always exert a dominant regulatory role.

TTP interacts with the basic RNA decay machinery

TTP promotes AMD by interacting with various components of the basic RNA decay machinery. Proteins reported to bind to TTP are summarized in Table 1. Since many of the interacting proteins are subunits of larger complexes, it is not always clear whether the interactions are direct or indirect. Also, we have not included proteins that interact with TTP in an RNA-dependent manner, since these RNase-sensitive interactions reflect the complex nature of mRNPs rather than specific partners of TTP.

Table 1
Protein partners interacting with TTP
Partner Function Reference 
14-3-3 Family of adaptor proteins: [38,39
  binds to phosphoserine containing motifs (Ser52 and Ser178 in mouse TTP)  
  inhibits TTP activity  
  stabilizes TTP protein  
  enhances cytoplasmic localization of TTP  
  prevents TTP from associating with stress granules  
MK2 MAPKAP kinase-2: [44
  directly phosphorylates TTP at Ser52 and Ser178 (mouse TTP)  
PP2A Protein phosphatase 2A, heterotrimer: [41
  competes with 14-3-3 protein  
  dephosphorylates TTP at Ser178 (mouse TTP)  
  activates TTP  
PM-Scl75 Subunit of the exosome (3′–5′-exoribonuclease complex): [18,22
  contains RNase PH domain  
Rrp4 Subunit of the exosome (3′–5′-exoribonuclease complex): [18,22
  contains KH and S1 RNA-binding domains  
Ccr4 Deadenylase, subunit of the Ccr4–Caf1–Not complex: [18
  contains exonuclease III domain  
  P-body component  
Dcp2 Subunit of the decapping complex: [18,19
  catalytically active decapping enzyme  
  P-body component  
Dcp1a Subunit of the decapping complex: [18
  enhancer of decapping  
  P-body component  
Edc3 Subunit of the decapping complex: [19
  enhancer of decapping  
  P-body component  
Hedls Subunit of the decapping complex: [19
  enhancer of decapping  
  P-body component  
Xrn1 5′–3′-exoribonuclease: [18
  P-body component  
Ago2, Ago4 Argonaute 2 and 4, subunits of the RNA-induced silencing complex: [20
  P-body component  
KSRP KH-type splicing regulatory protein: [25
  binds to and destabilizes ARE-containing mRNAs  
  TTP proposed to inhibit iNOS mRNA decay through binding to KSRP  
Nup214 Nuclear pore protein: [26
  interacts with TTP through the FG repeat-containing C-terminus  
Tax Retroviral oncoprotein: [27
  TTP inhibits the ability of Tax to transactivate LTR promoters  
  Tax interferes with TTP activity  
Partner Function Reference 
14-3-3 Family of adaptor proteins: [38,39
  binds to phosphoserine containing motifs (Ser52 and Ser178 in mouse TTP)  
  inhibits TTP activity  
  stabilizes TTP protein  
  enhances cytoplasmic localization of TTP  
  prevents TTP from associating with stress granules  
MK2 MAPKAP kinase-2: [44
  directly phosphorylates TTP at Ser52 and Ser178 (mouse TTP)  
PP2A Protein phosphatase 2A, heterotrimer: [41
  competes with 14-3-3 protein  
  dephosphorylates TTP at Ser178 (mouse TTP)  
  activates TTP  
PM-Scl75 Subunit of the exosome (3′–5′-exoribonuclease complex): [18,22
  contains RNase PH domain  
Rrp4 Subunit of the exosome (3′–5′-exoribonuclease complex): [18,22
  contains KH and S1 RNA-binding domains  
Ccr4 Deadenylase, subunit of the Ccr4–Caf1–Not complex: [18
  contains exonuclease III domain  
  P-body component  
Dcp2 Subunit of the decapping complex: [18,19
  catalytically active decapping enzyme  
  P-body component  
Dcp1a Subunit of the decapping complex: [18
  enhancer of decapping  
  P-body component  
Edc3 Subunit of the decapping complex: [19
  enhancer of decapping  
  P-body component  
Hedls Subunit of the decapping complex: [19
  enhancer of decapping  
  P-body component  
Xrn1 5′–3′-exoribonuclease: [18
  P-body component  
Ago2, Ago4 Argonaute 2 and 4, subunits of the RNA-induced silencing complex: [20
  P-body component  
KSRP KH-type splicing regulatory protein: [25
  binds to and destabilizes ARE-containing mRNAs  
  TTP proposed to inhibit iNOS mRNA decay through binding to KSRP  
Nup214 Nuclear pore protein: [26
  interacts with TTP through the FG repeat-containing C-terminus  
Tax Retroviral oncoprotein: [27
  TTP inhibits the ability of Tax to transactivate LTR promoters  
  Tax interferes with TTP activity  

TTP interacts with several protein components of P-bodies (processing bodies), which are small cytoplasmic foci that contain many enzymes required for mRNA decay [15]. Specific mRNAs are recruited to P-bodies, including transcripts that are translationally silenced by microRNAs and mRNAs targeted for decay by an ARE [16,17]. P-body-associated proteins that bind to TTP include Ccr4, a component of the Ccr4–Caf1–Not complex involved in the deadenylation of mRNAs [18]. Via its N-terminal domain, TTP interacts with components of the decapping complex including Dcp2, Dcp1a, Edc3 and Hedls [18,19]. Furthermore, TTP interacts with the 5′–3′-exonuclease Xrn1 [18], as well as with Ago2 and Ago4, central components of the RNA-induced silencing complex [20]. Since all of the above complexes are localized in P-bodies together with TTP [21], P-bodies may be sites where AMD occurs. Indeed, tethering of TTP to a reporter mRNA that does not contain an ARE is sufficient to target the mRNA to P-bodies and induce its rapid decay [17,18].

TTP also binds to RNA decay enzymes that are not components of P-bodies. TTP interacts with the exosome as shown by the association with two of its subunits, PM-Scl75 and Rrp4 [18,22]. The exosome is composed of at least ten exoribonucleases and RNA binding proteins, and is required for the processing and degradation of RNAs in the 3′–5′-direction [23]. TTP also activates the deadenylase PARN [poly(A)-specific ribonuclease], although a direct interaction between TTP and PARN was not demonstrated [24]. In addition, TTP binds to another ARE-binding protein, KSRP (KH-type splicing regulatory protein), and was proposed to increase iNOS [inducible NOS (nitric oxide synthase)] mRNA expression by inhibiting the destabilizing activity of KSRP [25].

Finally, TTP interacts with a few proteins that are not directly linked to RNA decay. This includes the nucleoporin Nup214, which may affect the distribution of TTP between the nucleus and the cytoplasm [26]. TTP also interacts with Tax, an oncoprotein expressed by leukaemogenic retroviruses such as HTLV-1 (human T-lymphotropic virus type 1). While TTP inhibits the transcriptional transactivating function of Tax, Tax in turn inhibits TTP and may thereby modulate cytokine expression in HTLV-1-infected cells [27].

Phosphorylation by MK2 {MAPKAP [MAPK (mitogen-activated protein kinase)-activated protein] kinase-2} inhibits TTP activity

AREs not only promote rapid mRNA decay, but also allow the stability of mRNAs to be regulated in response to extracellular cues. Typical targets of TTP (e.g. IL-2, GM-CSF and TNFα mRNAs) are rapidly degraded in unstimulated T-cells and macrophages, yet transiently stabilized in response to activation [2830]. Inhibition of AMD involves several signalling cascades including the JNK (c-Jun N-terminal kinase), p38-MAPK and PI3K (phosphoinositide 3-kinase) pathways [3134]. Macrophages stimulated by the bacterial product LPS (lipopolysaccharide) have been a very informative model to study the post-transcriptional induction of cytokines. In these cells, the p38-MAPK–MK2 pathway is of particular importance for cytokine expression. Macrophages from MK2−/− mice show severely reduced levels of TNFα, IL-1, IL-6 and IFNγ (interferon-γ), and further analysis revealed that MK2 controls both the stability and translation efficiency of cytokine mRNAs [35,36].

A major target of MK2 during immune activation is TTP. As shown in Figure 1, MK2 directly phosphorylates TTP at two serine residues (Ser52 and Ser178 in mouse TTP) [37]. Phosphorylation at these two sites allows binding of 14-3-3 adaptor proteins, which reduces the destabilizing activity of TTP [38,39]. The importance of 14-3-3 protein binding for TTP inhibition is illustrated by a non-phosphorylatable mutant that does not bind 14-3-3 protein. The TTP-AA mutant, when transfected into macrophages, is constitutively active as it prevents up-regulation of a TNFα 3′-UTR reporter gene in response to LPS [39]. Genetic evidence supports the notion that TTP is the primary target of MK2 for cytokine induction. In MK2−/− TTP−/−-double-knockout macrophages, the low TNFα levels in MK2−/− mice are restored to the high levels observed in TTP−/− mice [40]. This study also suggested that phosphorylation of Ser52 and Ser178 may reduce the affinity of TTP for the ARE. In addition, we speculate that protein–protein interactions by which TTP recruits the basic RNA decay machinery may also be affected by phosphorylation.

Control of ARE-mediated mRNA degradation by TTP

Figure 1
Control of ARE-mediated mRNA degradation by TTP

In the unphosphorylated state, TTP binds to the ARE and promotes rapid degradation of the mRNA. Phosphorylation of TTP by MK2 leads to binding of 14-3-3 adaptor proteins and stabilization of the ARE-containing target mRNA. Phosphorylation also prevents decay of the TTP protein, causes TTP to accumulate in the cytoplasm, and excludes TTP from stress granules. The phosphatase PP2A competes with 14-3-3 protein and causes dephosphorylation of TTP.

Figure 1
Control of ARE-mediated mRNA degradation by TTP

In the unphosphorylated state, TTP binds to the ARE and promotes rapid degradation of the mRNA. Phosphorylation of TTP by MK2 leads to binding of 14-3-3 adaptor proteins and stabilization of the ARE-containing target mRNA. Phosphorylation also prevents decay of the TTP protein, causes TTP to accumulate in the cytoplasm, and excludes TTP from stress granules. The phosphatase PP2A competes with 14-3-3 protein and causes dephosphorylation of TTP.

If MK2 inhibits TTP, then how does this protein get back to work? Recent evidence suggests that MK2 is counterbalanced by the phosphatase PP2A (protein phosphatase 2A), which directly competes with 14-3-3 protein for binding to TTP [41]. PP2A then dephosphorylates TTP at S178 (and possibly other serine/threonine residues) and thereby activates mRNA decay. This role of PP2A may be of particular importance during the second phase of macrophage stimulation when cytokine levels decrease and cytokine mRNAs are rapidly degraded.

MK2 controls export and protein stability of TTP

The interplay between the p38-MAPK–MK2 pathway and TTP is more intricate than a simple ‘MK2 inhibits TTP’ model would suggest. In several ways, MK2 is also an activator of TTP. First of all, TTP expression itself is strongly induced by LPS in macrophages. This is counterintuitive, since TTP as an inhibitor of cytokine expression is induced along with cytokines. Up-regulation of TTP is due in part to MK2-dependent stabilization of TTP mRNA, and in part to stabilization of the TTP protein [40]. Phosphorylation of TTP at Ser52 and Ser178 by MK2 directly prevents decay of the protein by the proteasome [42]. Secondly, 14-3-3 protein binding also promotes redistribution of TTP from the nucleus to the cytoplasm [38,42]. Taken together, the p38-MAPK–MK2 pathway exerts extensive control over TTP. Soon after stimulation of macrophages by LPS, MK2 is required for the full induction of TTP expression. By phosphorylating TTP at two critical serine residues, MK2 causes accumulation of the protein in the cytoplasm, yet keeps it in an inactive state. As a consequence, cytokine mRNAs are stabilized and can be efficiently translated during the first ‘on’ phase of cytokine induction. During the second phase when cytokine production is turned off, ample amounts of TTP are now ready in the cytoplasm to be activated through dephosphorylation by PP2A. This will lead to rapid degradation of target mRNAs and thereby contribute to the shutdown of cytokine production. Thus MK2 and PP2A appear to co-ordinate sequential events during the inflammatory response by controlling the expression, stability, localization and activity of TTP.

Stress granules and P-bodies

Maybe the most enigmatic aspect of TTP regulation is its localization in stress granules. Cells exposed to unfavourable conditions such as heat shock, oxidative stress or energy deprivation mount a stress response that involves shutdown of bulk mRNA translation. Arrest of translation correlates with the assembly of stress granules in the cytoplasm, large aggregates that contain the untranslated mRNAs together with stalled translation initiation factors [43]. During the stress response, TTP is recruited to stress granules, yet only under conditions where it is not phosphorylated and not bound by 14-3-3 protein [39]. This phenomenon can be visualized by live-cell video microscopy (see Supplementary data at http://www.biochemsoctrans.org/bst/036/bst0360491add.htm). This movie, two frames of which are depicted in Figure 2, demonstrates the exclusion of TTP from stress granules upon treatment of cells with arsenite, which causes activation of the p38-MAPK–MK2 cascade. In contrast with wt TTP, the TTP-AA mutant that cannot be phosphorylated by MK2 is not excluded from stress granules. Thus the active non-phosphorylated form of TTP has the ability to associate with stress granules. Having access to the pool of translationally stalled mRNAs may be important for the function of TTP.

TTP dissociates from stress granules on phosphorylation

Figure 2
TTP dissociates from stress granules on phosphorylation

COS7 cells were transiently transfected with RFP (red fluorescent protein)–TIA1 as a stress granule marker and either YFP (yellow fluorescent protein)–TTP-wt (upper panel) or YFP–TTP-AA (lower panel), a mutant that cannot be phosphorylated by MK2. Cells were treated with 0.5 mM arsenite to activate the p38-MAPK–MK2 cascade and monitored by live-cell imaging. Frames taken at 0 (A) and 20 (B) min are shown. Phosphorylation of YFP–TTP-wt causes the protein to dissociate from stress granules (arrowheads), whereas non-phosphorylatable YFP–TTP-AA remains concentrated in stress granules. The entire movie can be viewed at http://www.biochemsoctrans.org/bst/036/bst0360491add.htm.

Figure 2
TTP dissociates from stress granules on phosphorylation

COS7 cells were transiently transfected with RFP (red fluorescent protein)–TIA1 as a stress granule marker and either YFP (yellow fluorescent protein)–TTP-wt (upper panel) or YFP–TTP-AA (lower panel), a mutant that cannot be phosphorylated by MK2. Cells were treated with 0.5 mM arsenite to activate the p38-MAPK–MK2 cascade and monitored by live-cell imaging. Frames taken at 0 (A) and 20 (B) min are shown. Phosphorylation of YFP–TTP-wt causes the protein to dissociate from stress granules (arrowheads), whereas non-phosphorylatable YFP–TTP-AA remains concentrated in stress granules. The entire movie can be viewed at http://www.biochemsoctrans.org/bst/036/bst0360491add.htm.

As mentioned above, TTP also localizes to P-bodies [21]. In stressed cells, P-bodies make frequent yet transient contacts with stress granules. When TTP is overexpressed, the dynamics of these contacts changes dramatically as P-bodies become glued to stress granules [21]. On phosphorylation, TTP is excluded from stress granules and P-bodies are released from their tight association with stress granules (N. Kedersha, personal communication). Interestingly, TTP remains in P-bodies irrespective of its phosphorylation status. One interpretation of these observations is that contacts between stress granules and P-bodies may allow for the transit of stalled mRNAs to the decay compartment. When TTP is overexpressed and active (not phosphorylated), a large number of mRNAs will be targeted for decay and need to move from stress granules to P-bodies. According to this model, the increased flux of mRNAs leads to a tight association between the two compartments.

Conclusions

Over the last 10 years, genetic and biochemical evidence has been obtained for the central role the p38-MAPK–MK2–TTP axis plays in regulating cytokine expression at the post-transcriptional level. By controlling the activity, localization and stability of TTP, MK2 and PP2A co-ordinate sequential events during the on and off phases of cytokine expression. In addition, the study of this intricate regulatory network has provided insights into the principles that guide an mRNA from a state of active translation to a stalled mRNP and eventually towards final degradation. A better understanding of the underlying mechanisms will require that we resolve these processes with greater detail in time and space.

RNA UK 2008: Independent Meeting held at The Burnside Hotel, Bowness on Windermere, Cumbria, U.K., 18–20 January 2008. Organized and Edited by David Elliot (Newcastle, U.K.), Sarah Newbury (Sussex, U.K.) and Alison Tyson-Capper (Newcastle, U.K.).

Abbreviations

     
  • ARE

    AU-rich element

  •  
  • AMD

    ARE-mediated mRNA decay

  •  
  • GM-CSF

    granulocyte/macrophage colony-stimulating factor

  •  
  • HTLV-1

    human T-lymphotropic virus type 1

  •  
  • IL

    interleukin

  •  
  • iNOS

    inducible NOS (nitric oxide synthase)

  •  
  • KSRP

    KH-type splicing regulatory protein

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MAPKAP

    MAPK-activated protein

  •  
  • MK2

    MAPKAP kinase-2

  •  
  • PARN

    poly(A)-specific ribonuclease

  •  
  • PP2A

    protein phosphatase 2A

  •  
  • mRNP

    messenger ribonucleoprotein

  •  
  • P-bodies

    processing bodies

  •  
  • TNFα

    tumour necrosis factor α

  •  
  • TTP

    tristetraprolin

  •  
  • UTR

    untranslated region

  •  
  • wt

    wild-type

  •  
  • YFP

    yellow fluorescent protein

We thank Nancy Kedersha (Brigham and Women's Hospital, Boston, MA, U.S.A.) for sharing unpublished results and Paul Anderson (Brigham and Women's Hospital) for helpful discussions.

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Supplementary data