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Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Open AccessPublished:July 27, 2011DOI:https://doi.org/10.1074/jbc.M111.264754
      Post-transcriptional mechanisms play an important role in the control of inflammatory gene expression. The heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) triggers rapid degradation of mRNAs for various cytokines, chemokines, and other inflammation-related proteins by interacting with AU-rich elements (AREs) in the 3′-untranslated mRNA regions. In addition to destabilizing mRNAs, AU-rich elements can restrict their translation. Evidence that KSRP also participates in translational silencing was obtained in a screen comparing the polysome profiles of cells with siRNA-mediated depletion of KSRP with that of control cells. Among the group of mRNAs showing increased polysome association upon KSRP depletion are those of interleukin (IL)-6 and IL-1α as well as other ARE-containing transcripts. Redistribution of IL-6 mRNA to polysomes was associated with increased IL-6 protein secretion by the KSRP-depleted cells. Silencing of IL-6 and IL-1α mRNAs depended on their 3′-untranslated regions. The sequence essential for translational control of IL-6 mRNA and its interaction with KSRP was located to an ARE. KSRP-dependent silencing was reversed by IL-1, a strong inducer of IL-6 mRNA and protein expression. The results identify KSRP as a protein involved in ARE-mediated translational silencing. They suggest that KSRP restricts inflammatory gene expression not only by enhancing degradation of mRNAs but also by inhibiting translation, both functions that are counteracted by the proinflammatory cytokine IL-1.

      Introduction

      Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs)
      The abbreviations used are: ARE
      AU-rich element
      nt
      nucleotide(s)
      KSRP
      KH-type splicing regulatory protein
      qPCR
      quantitative PCR
      KH
      heterogeneous nuclear ribonucleoprotein K homology
      miRNA
      microRNA
      MAP
      mitogen-activated protein.
      that can impose rapid degradation and restrict translation (
      • Stoecklin G.
      • Anderson P.
      ,
      • Anderson P.
      ,
      • Khabar K.S.
      ). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (
      • Davis-Smyth T.
      • Duncan R.C.
      • Zheng T.
      • Michelotti G.
      • Levens D.
      ). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref.
      • Briata P.
      • Chen C.Y.
      • Giovarelli M.
      • Pasero M.
      • Trabucchi M.
      • Ramos A.
      • Gherzi R.
      ). Most recently it has been found to contribute to regulation of RNA 3′-end processing (
      • Danckwardt S.
      • Gantzert A.S.
      • Macher-Goeppinger S.
      • Probst H.C.
      • Gentzel M.
      • Wilm M.
      • Gröne H.J.
      • Schirmacher P.
      • Hentze M.W.
      • Kulozik A.E.
      ).
      KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (
      • Chen C.Y.
      • Gherzi R.
      • Ong S.E.
      • Chan E.L.
      • Raijmakers R.
      • Pruijn G.J.
      • Stoecklin G.
      • Moroni C.
      • Mann M.
      • Karin M.
      ,
      • Gherzi R.
      • Lee K.Y.
      • Briata P.
      • Wegmüller D.
      • Moroni C.
      • Karin M.
      • Chen C.Y.
      ). Ksrp−/− cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (
      • Lin W.J.
      • Zheng X.
      • Lin C.C.
      • Tsao J.
      • Zhu X.
      • Cody J.J.
      • Coleman J.M.
      • Gherzi R.
      • Luo M.
      • Townes T.M.
      • Parker J.N.
      • Chen C.Y.
      ). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs.
      • Briata P.
      • Forcales S.V.
      • Ponassi M.
      • Corte G.
      • Chen C.Y.
      • Karin M.
      • Puri P.L.
      • Gherzi R.
      ,
      • Gherzi R.
      • Trabucchi M.
      • Ponassi M.
      • Ruggiero T.
      • Corte G.
      • Moroni C.
      • Chen C.Y.
      • Khabar K.S.
      • Andersen J.S.
      • Briata P.
      ,
      • Linker K.
      • Pautz A.
      • Fechir M.
      • Hubrich T.
      • Greeve J.
      • Kleinert H.
      ,
      • Suswam E.A.
      • Nabors L.B.
      • Huang Y.
      • Yang X.
      • King P.H.
      ). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (
      • Winzen R.
      • Kracht M.
      • Ritter B.
      • Wilhelm A.
      • Chen C.Y.
      • Shyu A.B.
      • Müller M.
      • Gaestel M.
      • Resch K.
      • Holtmann H.
      ,
      • Winzen R.
      • Thakur B.K.
      • Dittrich-Breiholz O.
      • Shah M.
      • Redich N.
      • Dhamija S.
      • Kracht M.
      • Holtmann H.
      ), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (
      • Briata P.
      • Forcales S.V.
      • Ponassi M.
      • Corte G.
      • Chen C.Y.
      • Karin M.
      • Puri P.L.
      • Gherzi R.
      ).
      IL-6, originally cloned as 26-kDa protein (
      • Haegeman G.
      • Content J.
      • Volckaert G.
      • Derynck R.
      • Tavernier J.
      • Fiers W.
      ), IFN-β2 (
      • Zilberstein A.
      • Ruggieri R.
      • Korn J.H.
      • Revel M.
      ), and BSF-2 (
      • Hirano T.
      • Yasukawa K.
      • Harada H.
      • Taga T.
      • Watanabe Y.
      • Matsuda T.
      • Kashiwamura S.
      • Nakajima K.
      • Koyama K.
      • Iwamatsu A.
      • Tsunasawa S.
      • Sakiyama F.
      • Matsui H.
      • Takahara Y.
      • Taniguchi T.
      • Kishimoto T.
      ), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (
      • Kishimoto T.
      ,
      • Scheller J.
      • Chalaris A.
      • Schmidt-Arras D.
      • Rose-John S.
      ). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (
      • Kohase M.
      • Henriksen-DeStefano D.
      • May L.T.
      • Vilcek J.
      • Sehgal P.B.
      ) and IL-1 (
      • Content J.
      • De Wit L.
      • Poupart P.
      • Opdenakker G.
      • Van Damme J.
      • Billiau A.
      ). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (
      • Paschoud S.
      • Dogar A.M.
      • Kuntz C.
      • Grisoni-Neupert B.
      • Richman L.
      • Kühn L.C.
      ). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (
      • Winzen R.
      • Kracht M.
      • Ritter B.
      • Wilhelm A.
      • Chen C.Y.
      • Shyu A.B.
      • Müller M.
      • Gaestel M.
      • Resch K.
      • Holtmann H.
      ,
      • Neininger A.
      • Kontoyiannis D.
      • Kotlyarov A.
      • Winzen R.
      • Eckert R.
      • Volk H.D.
      • Holtmann H.
      • Kollias G.
      • Gaestel M.
      ). IL-6 expression is also controlled by miRNAs (
      • Iliopoulos D.
      • Hirsch H.A.
      • Struhl K.
      ,
      • Jones M.R.
      • Quinton L.J.
      • Blahna M.T.
      • Neilson J.R.
      • Fu S.
      • Ivanov A.R.
      • Wolf D.A.
      • Mizgerd J.P.
      ).
      Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of IL-6 (
      • Dhamija S.
      • Doerrie A.
      • Winzen R.
      • Dittrich-Breiholz O.
      • Taghipour A.
      • Kuehne N.
      • Kracht M.
      • Holtmann H.
      ). We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

      DISCUSSION

      KSRP participates in the control of gene expression in different ways, including the ARE-dependent rapid degradation of mRNAs and the maturation of miRNAs (
      • Briata P.
      • Chen C.Y.
      • Giovarelli M.
      • Pasero M.
      • Trabucchi M.
      • Ramos A.
      • Gherzi R.
      ). By studying IL-6 mRNA, we obtained evidence that KSRP also limits translation of mRNAs through direct interaction with AREs. siRNA-mediated knockdown of KSRP resulted in increased ribosome association of IL-6 mRNA according to polysome profiling by density gradient centrifugation (Fig. 1C). Furthermore, KSRP depletion caused a marked increase in IL-6 protein that clearly surpassed that of its mRNA (Fig. 1E). IL-6 mRNA contains AU-rich sequences that contribute to its rapid degradation (
      • Winzen R.
      • Kracht M.
      • Ritter B.
      • Wilhelm A.
      • Chen C.Y.
      • Shyu A.B.
      • Müller M.
      • Gaestel M.
      • Resch K.
      • Holtmann H.
      ,
      • Paschoud S.
      • Dogar A.M.
      • Kuntz C.
      • Grisoni-Neupert B.
      • Richman L.
      • Kühn L.C.
      ,
      • Neininger A.
      • Kontoyiannis D.
      • Kotlyarov A.
      • Winzen R.
      • Eckert R.
      • Volk H.D.
      • Holtmann H.
      • Kollias G.
      • Gaestel M.
      ,
      • Tonouchi N.
      • Koyama N.
      • Miwa K.
      ). The observations that KSRP-dependent translational silencing required an ARE (Fig. 4) and that KSRP interacted directly with the IL-6 mRNA in an ARE-dependent manner (Fig. 5D) strongly suggest that KSRP binding to the ARE suppresses translation.
      Translational repression by AREs was first observed for RNAs injected into Xenopus oocytes under conditions in which the RNAs were stable (
      • Kruys V.
      • Marinx O.
      • Shaw G.
      • Deschamps J.
      • Huez G.
      ). The RNA-binding protein TIA-1 was identified as a translational silencer selective for TNF-α mRNA, whereas its deletion hardly affected levels of certain other cytokines, including IL-6 (
      • Piecyk M.
      • Wax S.
      • Beck A.R.
      • Kedersha N.
      • Gupta M.
      • Maritim B.
      • Chen S.
      • Gueydan C.
      • Kruys V.
      • Streuli M.
      • Anderson P.
      ). Activation by lipopolysaccharide can release translational silencing of TNFα mRNA through p38 MAP kinase and its substrate kinase MK2 (
      • Kotlyarov A.
      • Neininger A.
      • Schubert C.
      • Eckert R.
      • Birchmeier C.
      • Volk H.D.
      • Gaestel M.
      ,
      • Prichett W.
      • Hand A.
      • Sheilds J.
      • Dunnington D.
      ). Of note, decreased polysome association of TNF-α mRNA upon inhibition of p38 MAP kinase was still observed in cells lacking TIA-1 (
      • Piecyk M.
      • Wax S.
      • Beck A.R.
      • Kedersha N.
      • Gupta M.
      • Maritim B.
      • Chen S.
      • Gueydan C.
      • Kruys V.
      • Streuli M.
      • Anderson P.
      ), indicating that TIA-1 is not the target of signals increasing translation. It is tempting to speculate that KSRP, a substrate of p38 MAP kinase (
      • Briata P.
      • Forcales S.V.
      • Ponassi M.
      • Corte G.
      • Chen C.Y.
      • Karin M.
      • Puri P.L.
      • Gherzi R.
      ), represents a signal-controlled component of translational silencing of ARE-containing mRNAs. In fact, interaction between TIA-1 and KSRP has been reported (
      • Rothé F.
      • Gueydan C.
      • Bellefroid E.
      • Huez G.
      • Kruys V.
      ). Besides TIA-1, other proteins have been observed to influence translation of ARE-containing mRNAs (Refs.
      • Stoecklin G.
      • Anderson P.
      ,
      • Anderson P.
      ,
      • Khabar K.S.
      and references therein).
      KSRP has been demonstrated to regulate maturation of a group of miRNAs, including miR-26b and let-7a (
      • Trabucchi M.
      • Briata P.
      • Garcia-Mayoral M.
      • Haase A.D.
      • Filipowicz W.
      • Ramos A.
      • Gherzi R.
      • Rosenfeld M.G.
      ). We did not obtain evidence for the contribution of these miRNAs, which have been reported to control IL-6 expression (
      • Iliopoulos D.
      • Hirsch H.A.
      • Struhl K.
      ,
      • Jones M.R.
      • Quinton L.J.
      • Blahna M.T.
      • Neilson J.R.
      • Fu S.
      • Ivanov A.R.
      • Wolf D.A.
      • Mizgerd J.P.
      ), to restricted translation of IL-6 mRNA in our experimental setting. However, it is well possible that under different conditions, e.g. DNA damage, which activates the processing function of KSRP via ATM kinase (
      • Zhang X.
      • Wan G.
      • Berger F.G.
      • He X.
      • Lu X.
      ), KSRP exerts an even stronger suppression of translation through the combination of direct interaction and processing of miRNAs in the case of IL-6 but also other mRNAs that contain both target sequences of KSRP-regulated miRNAs and binding sites for KSRP itself.
      In an attempt to identify other targets regulated by KSRP, pools of polysomal and subpolysomal fractions from KSRP-depleted and control cells were compared by microarray analysis. Cells were treated with IL-1 to include analysis of mRNAs that are only expressed in response to inflammatory stimuli. Although IL-1 can already increase polysome association, a further increase upon KSRP depletion was noted for IL-6, IL-1α, and other mRNAs. A likely explanation is that the IL-1-induced redistribution to polysomes and decrease in KSRP binding are partial (Figs. 4C and 5A, respectively). Furthermore, IL-1 treatment was for 2 h in these assays, a period after which some effects of IL-1 are already reversed (not shown). However, it is possible that the effect of IL-1 is stronger for certain mRNAs that therefore might remain undetected in our screen.
      KSRP targets defined by association with KSRP in pulldown experiments and increased amounts upon KSRP depletion (
      • Winzen R.
      • Thakur B.K.
      • Dittrich-Breiholz O.
      • Shah M.
      • Redich N.
      • Dhamija S.
      • Kracht M.
      • Holtmann H.
      ) are enriched among the mRNAs that show increased polysome association in KSRP-depleted cells. This argues for a mechanistic link between translational silencing and destabilization. On the other hand, most of the transcripts in Table 1 are not among the targets of KSRP destabilization identified earlier. This is not unexpected because the screen for increased ribosome association following KSRP depletion should not only detect mRNAs controlled by KSRP directly but also mRNAs that KSRP regulates indirectly by promoting maturation of miRNAs that target them (
      • Trabucchi M.
      • Briata P.
      • Garcia-Mayoral M.
      • Haase A.D.
      • Filipowicz W.
      • Ramos A.
      • Gherzi R.
      • Rosenfeld M.G.
      ,
      • Ruggiero T.
      • Trabucchi M.
      • De Santa F.
      • Zupo S.
      • Harfe B.D.
      • McManus M.T.
      • Rosenfeld M.G.
      • Briata P.
      • Gherzi R.
      ). To what extent KSRP can restrict mRNA translation also independently of AREs and destabilization and of its effect on miRNA maturation is not clear at present. According to one report, KSRP negatively regulates viral translation by interacting with an internal ribosomal entry site (
      • Lin J.Y.
      • Li M.L.
      • Shih S.R.
      ). Recently, regulation of translation has also been reported for the other members of the far upstream sequence element-binding proteins FUBP1 (
      • Gau B.H.
      • Chen T.M.
      • Shih Y.H.
      • Sun H.S.
      ) and FUBP3 (
      • Olanich M.E.
      • Moss B.L.
      • Piwnica-Worms D.
      • Townsend R.R.
      • Weber J.D.
      ).
      Several groups including our own have shown that IL-1 can increase inflammatory gene expression by stabilizing mRNAs (Refs.
      • Suswam E.A.
      • Nabors L.B.
      • Huang Y.
      • Yang X.
      • King P.H.
      ,
      • Winzen R.
      • Kracht M.
      • Ritter B.
      • Wilhelm A.
      • Chen C.Y.
      • Shyu A.B.
      • Müller M.
      • Gaestel M.
      • Resch K.
      • Holtmann H.
      , and
      • Tebo J.
      • Der S.
      • Frevel M.
      • Khabar K.S.
      • Williams B.R.
      • Hamilton T.A.
      ) and references therein). Among them are IL-6 mRNA and other targets of KSRP-dependent destabilization (
      • Winzen R.
      • Thakur B.K.
      • Dittrich-Breiholz O.
      • Shah M.
      • Redich N.
      • Dhamija S.
      • Kracht M.
      • Holtmann H.
      ). Recently, we have provided evidence that IL-1 can exert a dual effect on post-transcriptional control of several mRNAs: stabilization and increased translation (
      • Dhamija S.
      • Doerrie A.
      • Winzen R.
      • Dittrich-Breiholz O.
      • Taghipour A.
      • Kuehne N.
      • Kracht M.
      • Holtmann H.
      ). IL-1 interfered with KSRP-dependent translational silencing of IL-6 mRNA (Fig. 4). Like IL-1-induced stabilization, this might be explained by decreased KSRP binding through activation of p38 MAP kinase. However, other mRNAs regulated in both ways by IL-1 were not significantly affected by KSRP knockdown and thus are unlikely to be targets of KSRP (data not shown).
      Taken together, the results presented here demonstrate a role for KSRP in the ARE-dependent translational silencing of IL-6 and IL-1α mRNA and suggest that IL-1-induced interference with KSRP function not only contributes to mRNA stabilization but also to the recently observed translational activation exerted by this cytokine. These results support the importance of KSRP as a negative regulator of inflammation.

      Acknowledgments

      We thank Monika Barsch and Heike Schneider for technical assistance. We are grateful to Ching-Yi Chen for the gift of antibodies against KSRP and to Hermann Bujard for plasmids.

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