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Journal of Inflammation
Published in: Journal of Inflammation 1/2015

Open Access 01-12-2015 | Research

Functional regulation of Zfp36l1 and Zfp36l2 in response to lipopolysaccharide in mouse RAW264.7 macrophages

Authors: Kuan-Ting Wang, Hsin-Hui Wang, Yan-Yun Wu, Yu-Lun Su, Pei-Yu Chiang, Nien-Yi Lin, Shun-Chang Wang, Geen-Dong Chang, Ching-Jin Chang

Published in: Journal of Inflammation | Issue 1/2015

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Abstract

Background

The tristetraprolin (TTP) family of mRNA-binding proteins contains three major members, Ttp, Zfp36l1, and Zfp36l2. Ttp down-regulates the stability of AU-rich element–containing mRNAs and functions as an anti-inflammation regulator.

Methods

To examine whether other TTP family proteins also play roles in the inflammatory response, their expression profiles and the possible mRNA targets were determined in the knockdown cells.

Results

Ttp mRNA and protein were highly induced by lipopolysaccharide (LPS), whereas Zfp36l1 and Zfp36l2 mRNAs were down-regulated and their proteins were phosphorylated during early lipopolysaccharide stimulation. Biochemical and functional analyses exhibited that the decrease of Zfp36l2 mRNA was cross-regulated by Ttp. Knockdown of Zfp36l1 and Zfp36l2 increased the basal level of Mkp-1 mRNAs by prolonging its half-life. Increasing the expression of Mkp-1 inhibited the activation of p38 MAPK under lipopolysaccharide stimulation and down-regulated Tnfα, and Ttp mRNA. In addition, hyper-phosphorylation of Zfp36l1 might stabilize Mkp-1 expression by forming a complex with the adapter protein 14-3-3 and decreasing the interaction with deadenylase Caf1a.

Conclusions

Our findings imply that the expression and phosphorylation of Zfp36l1 and Zfp36l2 may modulate the basal level of Mkp-1 mRNA to control p38 MAPK activity during lipopolysaccharide stimulation, which would affect the inflammatory mediators production. Zfp36l1 and Zfp36l2 are important regulators of the innate immune response.
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Literature
1.
Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689–737.PubMedCrossRef
2.
Clark AR, Dean JL, Saklatvala J. Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett. 2003;546:37–44.PubMedCrossRef
3.
Dean JL, Sully G, Clark AR, Saklatvala J. The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal. 2004;16:1113–21.PubMedCrossRef
4.
Kracht M, Saklatvala J. Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine. 2002;20:91–106.PubMedCrossRef
5.
6.
Sanduja S, Blanco FF, Young LE, Kaza V, Dixon DA. The role of tristetraprolin in cancer and inflammation. Front Biosci. 2012;17:174–88.CrossRef
7.
Slack DN, Seternes OM, Gabrielsen M, Keyse SM. Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1. J Biol Chem. 2001;276:16491–500.PubMedCrossRef
8.
Hammer M, Mages J, Dietrich H, Servatius A, Howells N, Cato AC, et al. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J Exp Med. 2006;203:15–20.PubMedCentralPubMedCrossRef
9.
Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA, Bennett AM, et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A. 2006;103:2274–9.PubMedCentralPubMedCrossRef
10.
Zhao Q, Wang X, Nelin LD, Yao Y, Matta R, Manson ME, et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J Exp Med. 2006;203:131–40.PubMedCentralPubMedCrossRef
11.
Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA, Oravecz T. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 2006;176:1899–907.PubMedCrossRef
12.
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, et al. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 1996;4:445–54.PubMedCrossRef
13.
Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998;281:1001–5.PubMedCrossRef
14.
Zubiaga AM, Belasco JG, Greenberg ME. The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation. Mol Cell Biol. 1995;15:2219–30.PubMedCentralPubMed
15.
Lai WS, Carballo E, Thorn JM, Kennington EA, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. J Biol Chem. 2000;275:17827–37.PubMedCrossRef
16.
Rowlett RM, Chrestensen CA, Schroeder MJ, Harp MG, Pelo JW, Shabanowitz J, et al. Inhibition of tristetraprolin deadenylation by poly(A) binding protein. Am J Physiol Gastrointest Liver Physiol. 2008;295:G421–430.PubMedCentralPubMedCrossRef
17.
Gomperts M, Pascall JC, Brown KD. The nucleotide sequence of a cDNA encoding an EGF-inducible gene indicates the existence of a new family of mitogen-induced genes. Oncogene. 1990;5:1081–3.PubMed
18.
Varnum BC, Ma QF, Chi TH, Fletcher B, Herschman HR. The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat. Mol Cell Biol. 1991;11:1754–8.PubMedCentralPubMed
19.
Blackshear PJ, Phillips RS, Ghosh S, Ramos SB, Richfield EK, Lai WS. Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins. Biol Reprod. 2005;73:297–307.PubMedCrossRef
20.
Lai WS, Kennington EA, Blackshear PJ. Tristetraprolin and its family members can promote the cell-free deadenylation of AU-rich element-containing mRNAs by poly(A) ribonuclease. Mol Cell Biol. 2003;23:3798–812.PubMedCentralPubMedCrossRef
21.
Carrick DM, Blackshear PJ. Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines. Arch Biochem Biophys. 2007;462:278–85.PubMedCrossRef
22.
Stumpo DJ, Byrd NA, Phillips RS, Ghosh S, Maronpot RR, Castranio T, et al. Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family. Mol Cell Biol. 2004;24:6445–55.PubMedCentralPubMedCrossRef
23.
Ramos SB, Stumpo DJ, Kennington EA, Phillips RS, Bock CB, Ribeiro-Neto F, et al. The CCCH tandem zinc-finger protein Zfp36l2 is crucial for female fertility and early embryonic development. Development. 2004;131:4883–93.PubMedCrossRef
24.
Stumpo DJ, Broxmeyer HE, Ward T, Cooper S, Hangoc G, Chung YJ, et al. Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis. Blood. 2009;114:2401–10.PubMedCentralPubMedCrossRef
25.
Chen YL, Huang YL, Lin NY, Chen HC, Chiu WC, Chang CJ. Differential regulation of ARE-mediated TNFalpha and IL-1beta mRNA stability by lipopolysaccharide in RAW264.7 cells. Biochem Biophys Res Commun. 2006;346:160–8.PubMedCrossRef
26.
Lin NY, Lin TY, Yang WH, Wang SC, Wang KT, Su YL, et al. Differential expression and functional analysis of the tristetraprolin family during early differentiation of 3 T3-L1 preadipocytes. Int J Biol Sci. 2012;8:761–77.PubMedCentralPubMedCrossRef
27.
Lin NY, Lin CT, Chang CJ. Modulation of immediate early gene expression by tristetraprolin in the differentiation of 3 T3-L1 cells. Biochem Biophys Res Commun. 2008;365:69–74.PubMedCrossRef
28.
Chen YL, Jiang YW, Su YL, Lee SC, Chang MS, Chang CJ. Transcriptional regulation of tristetraprolin by NF-kappaB signaling in LPS-stimulated macrophages. Mol Biol Rep. 2013;40:2867–77.PubMedCrossRef
29.
Emmons J, Townley-Tilson WH, Deleault KM, Skinner SJ, Gross RH, Whitfield ML, et al. Identification of TTP mRNA targets in human dendritic cells reveals TTP as a critical regulator of dendritic cell maturation. RNA. 2008;14:888–902.PubMedCentralPubMedCrossRef
30.
Hao S, Baltimore D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat Immunol. 2009;10:281–8.PubMedCentralPubMedCrossRef
31.
Sandler H, Kreth J, Timmers HT, Stoecklin G. Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for degradation by tristetraprolin. Nucleic Acids Res. 2011;39:4373–86.PubMedCentralPubMedCrossRef
32.
Marchese FP, Aubareda A, Tudor C, Saklatvala J, Clark AR, Dean JL. MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J Biol Chem. 2010;285:27590–600.PubMedCentralPubMedCrossRef
33.
Clement SL, Scheckel C, Stoecklin G, Lykke-Andersen J. Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol Cell Biol. 2011;31:256–66.PubMedCentralPubMedCrossRef
34.
Fabian MR, Frank F, Rouya C, Siddiqui N, Lai WS, Karetnikov A, et al. Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin. Nat Struct Mol Biol. 2013;20:735–9.PubMedCrossRef
35.
Blackshear PJ, Perera L. Phylogenetic distribution and evolution of the linked RNA-binding and NOT1-binding domains in the tristetraprolin Family of Tandem CCCH Zinc finger proteins. J Interferon Cytokine Res. 2014;34:297–306.PubMedCentralPubMedCrossRef
36.
Adachi S, Homoto M, Tanaka R, Hioki Y, Murakami H, Suga H, et al. ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway. Nucleic Acids Res. 2014;42:10037–49.PubMedCentralPubMedCrossRef
37.
Schmidlin M, Lu M, Leuenberger SA, Stoecklin G, Mallaun M, Gross B, et al. The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J. 2004;23:4760–9.PubMedCentralPubMedCrossRef
38.
Maitra S, Chou CF, Luber CA, Lee KY, Mann M, Chen CY. The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase-activated protein kinase 2. RNA. 2008;14:950–9.PubMedCentralPubMedCrossRef
39.
Chen P, Li J, Barnes J, Kokkonen GC, Lee JC, Liu Y. Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J Immunol. 2002;169:6408–16.PubMedCrossRef
40.
Brooks SA, Blackshear PJ. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim Biophys Acta. 1829;2013:666–79.
41.
Liang J, Song W, Tromp G, Kolattukudy PE, Fu M. Genome-wide survey and expression profiling of CCCH-zinc finger family reveals a functional module in macrophage activation. PLoS One. 2008;3:e2880.PubMedCentralPubMedCrossRef
42.
Cao H, Urban Jr JF, Anderson RA. Cinnamon polyphenol extract affects immune responses by regulating anti- and proinflammatory and glucose transporter gene expression in mouse macrophages. J Nutr. 2008;138:833–40.PubMed
43.
Martinez-Pastor M, Vergara SV, Puig S, Thiele DJ. Negative feedback regulation of the yeast CTH1 and CTH2 mRNA binding proteins is required for adaptation to iron deficiency and iron supplementation. Mol Cell Biol. 2013;33:2178–87.PubMedCentralPubMedCrossRef
44.
Brook M, Tchen CR, Santalucia T, McIlrath J, Arthur JS, Saklatvala J, et al. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol. 2006;26:2408–18.PubMedCentralPubMedCrossRef
45.
Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber AD, Radzioch D, et al. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol. 2006;26:2399–407.PubMedCentralPubMedCrossRef
46.
Ramos SB. Characterization of DeltaN-Zfp36l2 mutant associated with arrest of early embryonic development and female infertility. J Biol Chem. 2012;287:13116–27.PubMedCentralPubMedCrossRef
47.
Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, et al. A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol. 2004;173:6928–37.PubMedCrossRef
48.
Marra F, Delogu W, Petrai I, Pastacaldi S, Bonacchi A, Efsen E, et al. Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G18–26.PubMedCrossRef
49.
Shepherd EG, Zhao Q, Welty SE, Hansen TN, Smith CV, Liu Y. The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages. J Biol Chem. 2004;279:54023–31.PubMedCrossRef
50.
Tchen CR, Brook M, Saklatvala J, Clark AR. The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself. J Biol Chem. 2004;279:32393–400.PubMedCrossRef
51.
Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR. Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol. 2001;21:6461–9.PubMedCentralPubMedCrossRef
52.
53.
Ciais D, Cherradi N, Bailly S, Grenier E, Berra E, Pouyssegur J, et al. Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Oncogene. 2004;23:8673–80.PubMedCrossRef
54.
Duan H, Cherradi N, Feige JJ, Jefcoate C. cAMP-dependent posttranscriptional regulation of steroidogenic acute regulatory (STAR) protein by the zinc finger protein ZFP36L1/TIS11b. Mol Endocrinol. 2009;23:497–509.PubMedCentralPubMedCrossRef
55.
Stoecklin G, Colombi M, Raineri I, Leuenberger S, Mallaun M, Schmidlin M, et al. Functional cloning of BRF1, a regulator of ARE-dependent mRNA turnover. EMBO J. 2002;21:4709–18.PubMedCentralPubMedCrossRef
56.
Lai WS, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly(A) tail. J Biol Chem. 2001;276:23144–54.PubMedCrossRef
57.
Lai WS, Kennington EA, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA: non-binding tristetraprolin mutants exert an inhibitory effect on degradation of AU-rich element-containing mRNAs. J Biol Chem. 2002;277:9606–13.PubMedCrossRef
58.
Ivanov P, Anderson P. Post-transcriptional regulatory networks in immunity. Immunol Rev. 2013;253:253–72.PubMedCrossRef
59.
Iwasaki H, Takeuchi O, Teraguchi S, Matsushita K, Uehata T, Kuniyoshi K, et al. The IkappaB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 2011;12:1167–75.PubMedCrossRef
Metadata
Title
Functional regulation of Zfp36l1 and Zfp36l2 in response to lipopolysaccharide in mouse RAW264.7 macrophages
Authors
Kuan-Ting Wang
Hsin-Hui Wang
Yan-Yun Wu
Yu-Lun Su
Pei-Yu Chiang
Nien-Yi Lin
Shun-Chang Wang
Geen-Dong Chang
Ching-Jin Chang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2015
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-015-0088-x

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