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IL-1-induced Post-transcriptional Mechanisms Target Overlapping Translational Silencing and Destabilizing Elements in IκBζ mRNA*[S]

Open AccessPublished:September 01, 2010DOI:https://doi.org/10.1074/jbc.M110.146365
      The inflammatory cytokine IL-1 induces profound changes in gene expression. This is contributed in part by activating translation of a distinct set of mRNAs, including IκBζ, as indicated by genome-wide analysis of changes in ribosomal occupancy in IL-1α-treated HeLa cells. Polysome profiling of IκBζ mRNA and reporter mRNAs carrying its 3′ UTR indicated poor translation in unstimulated cells. 3′ UTR-mediated translational silencing was confirmed by suppression of luciferase activity. Translational silencing was unaffected by replacing the poly(A) tail with a histone stem-loop, but lost under conditions of cap-independent internal initiation. IL-1 treatment of the cells caused profound shifts of endogenous and reporter mRNAs to polysome fractions and relieved suppression of luciferase activity. IL-1 also inhibited rapid mRNA degradation. Both translational activation and mRNA stabilization involved IRAK1 and -2 but occurred independently of the p38 MAPK pathway, which is known to target certain other post-transcriptional mechanisms. The translational silencing RNA element contains the destabilizing element but requires additional 5′ sequences and is impaired by mutations that leave destabilization unaffected. These differences in function are associated with differential changes in protein binding in vitro. Thus, rapid degradation occurs independently of the translational silencing effect. The results provide evidence for a novel mode of post-transcriptional control by IL-1, which impinges on the time course and pattern of IL-1-induced gene expression.

      Introduction

      Members of the IL-1 family of cytokines are intricately involved in inflammatory and immune responses (
      • Dinarello C.A.
      ). The founding members IL-1α and -β exert their multiple activities by binding to the same species of heterodimeric cell surface receptors present on virtually all nucleated cells. Consequences of their activation include changes in expression of numerous genes through activation of NF-κB and the JNK and p38 MAPK cascades (
      • O'Neill L.A.
      ,
      • Verstrepen L.
      • Bekaert T.
      • Chau T.L.
      • Tavernier J.
      • Chariot A.
      • Beyaert R.
      ,
      • Gaestel M.
      • Kotlyarov A.
      • Kracht M.
      ,
      • Weber A.
      • Wasiliew P.
      • Kracht M.
      ). In addition to transcriptional activation, post-transcriptional mechanisms have been reported to contribute to these changes. mRNA stabilization in response to IL-1 as well as LPS and other inflammatory activators depends on the p38 MAPK/MK2 pathway, which affects proteins that control degradation of mRNAs through selective binding to AU-rich elements (AREs)
      The abbreviations used are: ARE
      AU-rich element
      DSE
      destabilizing element
      IRES
      internal ribosome entry site
      nt
      nucleotides
      RT-qPCR
      reverse transcription and quantitative PCR
      TSE
      translational silencing element
      miR
      microRNA
      SL1 to -5
      stem-loops 1–5, respectively.
      (
      • Anderson P.
      ,
      • Stoecklin G.
      • Anderson P.
      ). The PI3K and JNK pathways have been reported as well to lead to stabilization of mRNAs (
      • Chen C.Y.
      • Gherzi R.
      • Andersen J.S.
      • Gaietta G.
      • Jürchott K.
      • Royer H.D.
      • Mann M.
      • Karin M.
      ,
      • Gherzi R.
      • Trabucchi M.
      • Ponassi M.
      • Ruggiero T.
      • Corte G.
      • Moroni C.
      • Chen C.Y.
      • Khabar K.S.
      • Andersen J.S.
      • Briata P.
      ). In addition, IL-1 induces stabilization of several mRNAs independently of TRAF6/p38/MK2 through an as yet unidentified signaling pathway downstream of IRAK1 (
      • Hartupee J.
      • Li X.
      • Hamilton T.
      ).
      The amount of a protein synthesized by the cell in a given condition is finally controlled at the level of translation by mechanisms related to those controlling mRNA degradation (
      • Buchan J.R.
      • Parker R.
      ). Translational control of gene expression can affect most RNAs as an adaptation of general protein synthesis to cell growth stimulation or stress conditions, or it can specifically target a small group of mRNAs (
      • Gebauer F.
      • Hentze M.W.
      ,
      • Sonenberg N.
      • Hinnebusch A.G.
      ). This study provides an example for the latter. Taking a microarray-based approach to investigate the effect of IL-1 on translation, we obtained evidence that a set of functionally related mRNAs is translationally activated by IL-1. In one of them, the mRNA of IκBζ, a specific IL-1-controlled translational silencing element was identified.
      IκBζ (NFKBIZ, also termed MAIL or INAP) was identified as a protein induced by LPS or IL-1 (
      • Haruta H.
      • Kato A.
      • Todokoro K.
      ,
      • Kitamura H.
      • Kanehira K.
      • Okita K.
      • Morimatsu M.
      • Saito M.
      ,
      • Yamazaki S.
      • Muta T.
      • Takeshige K.
      ) but not induced (
      • Haruta H.
      • Kato A.
      • Todokoro K.
      ,
      • Yamazaki S.
      • Muta T.
      • Takeshige K.
      ) or only weakly induced by TNF (
      • Totzke G.
      • Essmann F.
      • Pohlmann S.
      • Lindenblatt C.
      • Jänicke R.U.
      • Schulze-Osthoff K.
      ). IκBζ is localized in the nucleus and, unlike classical IκB proteins, is not degraded upon cell stimulation (
      • Totzke G.
      • Essmann F.
      • Pohlmann S.
      • Lindenblatt C.
      • Jänicke R.U.
      • Schulze-Osthoff K.
      ). Although negative effects on NF-κB activity have been observed (
      • Yamazaki S.
      • Muta T.
      • Takeshige K.
      ,
      • Totzke G.
      • Essmann F.
      • Pohlmann S.
      • Lindenblatt C.
      • Jänicke R.U.
      • Schulze-Osthoff K.
      ), IκBζ was reported to potentiate LPS-induced IL-6 formation (
      • Kitamura H.
      • Kanehira K.
      • Okita K.
      • Morimatsu M.
      • Saito M.
      ). Correspondingly, deletion of the IκBζ gene in mice resulted in impaired expression of IL-6 as well as GM-CSF and the p40 subunit of IL-12 (
      • Yamamoto M.
      • Yamazaki S.
      • Uematsu S.
      • Sato S.
      • Hemmi H.
      • Hoshino K.
      • Kaisho T.
      • Kuwata H.
      • Takeuchi O.
      • Takeshige K.
      • Saitoh T.
      • Yamaoka S.
      • Yamamoto N.
      • Yamamoto S.
      • Muta T.
      • Takeda K.
      • Akira S.
      ). IκBζ−/− mice also develop a severe atopic dermatitis-like disease (
      • Shiina T.
      • Konno A.
      • Oonuma T.
      • Kitamura H.
      • Imaoka K.
      • Takeda N.
      • Todokoro K.
      • Morimatsu M.
      ) and show defective development of the IL-17-producing TH17 T cell subset (
      • Okamoto K.
      • Iwai Y.
      • Oh-Hora M.
      • Yamamoto M.
      • Morio T.
      • Aoki K.
      • Ohya K.
      • Jetten A.M.
      • Akira S.
      • Muta T.
      • Takayanagi H.
      ). Further studies confirmed that IκBζ can suppress certain genes while being required for the expression of others (
      • Matsuo S.
      • Yamazaki S.
      • Takeshige K.
      • Muta T.
      ,
      • Kayama H.
      • Ramirez-Carrozzi V.R.
      • Yamamoto M.
      • Mizutani T.
      • Kuwata H.
      • Iba H.
      • Matsumoto M.
      • Honda K.
      • Smale S.T.
      • Takeda K.
      ,
      • Yamazaki S.
      • Matsuo S.
      • Muta T.
      • Yamamoto M.
      • Akira S.
      • Takeshige K.
      ). The comparatively poor induction of IκBζ by TNF might explain in part differences in the induction of genes between TNF and IL-1 or LPS, as has been observed for IL-1-specific induction of neutrophil gelatinase-associated lipocalin and β-defensin 2 in a lung epithelial cell line (
      • Cowland J.B.
      • Muta T.
      • Borregaard N.
      ,
      • Karlsen J.R.
      • Borregaard N.
      • Cowland J.B.
      ). Our results suggest that a translational control mechanism activated by IL-1 facilitates expression of IκBζ, which in turn controls expression of a subset of IL-1-regulated genes.

      DISCUSSION

      Ribosome association of an mRNA is considered as a general measure of its translational activity (
      • Preiss T.
      • Baron-Benhamou J.
      • Ansorge W.
      • Hentze M.W.
      ,
      • Mathews M.B.
      • Sonenberg N.
      • Hershey J.B.
      ). The combination of analyzing ribosome association in sucrose gradients and quantifying mRNAs on microarrays has been successfully used to obtain genome-wide information on translationally regulated mRNAs (
      • Preiss T.
      • Baron-Benhamou J.
      • Ansorge W.
      • Hentze M.W.
      ,
      • Arava Y.
      • Wang Y.
      • Storey J.D.
      • Liu C.L.
      • Brown P.O.
      • Herschlag D.
      ,
      • Brown V.
      • Jin P.
      • Ceman S.
      • Darnell J.C.
      • O'Donnell W.T.
      • Tenenbaum S.A.
      • Jin X.
      • Feng Y.
      • Wilkinson K.D.
      • Keene J.D.
      • Darnell R.B.
      • Warren S.T.
      ). Taking this approach, we have identified a small group of mRNAs that exhibit increased ribosome association in response to IL-1 (Table 1, Fig. 1, and supplemental Fig. S1).
      For IκBζ mRNA, the region mediating this effect could be localized to a highly conserved TSE encompassing nt 2273–2425 of its 3′ UTR. No obvious homology was observed when comparing the TSE with 3′ UTR sequences of the other transcripts translationally controlled by IL-1. In the murine IκBζ transcript, the region corresponding to the TSE has been reported to mediate post-transcriptional control; however, the contribution of mRNA stability versus translation was not examined (
      • Watanabe S.
      • Takeshige K.
      • Muta T.
      ). Within the human TSE, nt 2333–2425 contain a DSE that mediates rapid degradation under basal conditions and stabilization in response to IL-1 (Fig. 5). Thus, partly overlapping RNA elements mediate control of RNA stability and translation, the latter of which appears much more effective under the conditions applied here (Fig. 6E). The DSE contains only one AUUUA motif typical for AREs, and the neighboring sequences do not indicate a classical ARE. The function of the DSE could be distinguished from that of the TSE, based on several deletions and mutations that left destabilization unaffected but abolished translational silencing. Thus, translational silencing of the IκBζ mRNA is not a prerequisite of rapid degradation. This argues against a mechanism controlling IκBζ mRNA in which a translational silencing protein recruits a destabilizing protein as recently reported for TIA1 and KSRP (
      • Yamasaki S.
      • Stoecklin G.
      • Kedersha N.
      • Simarro M.
      • Anderson P.
      ). We cannot exclude the reverse situation, that a destabilizing mRNA-interacting protein recruits a translational silencer. The differential loss of binding of proteins to the TSE concomitant to selective loss of function upon truncation/mutation supports the involvement of functionally different proteins in TSE and DSE activity. Further studies are under way to clarify this point.
      Unlike destabilization, the function of the TSE appears to depend on conserved secondary structure elements. In particular, destroying stem-loop structure 3 (Fig. 6C) by mutations in either strand of the stem shifts the gradient distribution of the respective reporter mRNA to polysome-containing fractions. One of these mutations, SL3a, also destroys the seed region for microRNA 124a (miR-124a), which has recently been shown to control IκBζ translation (
      • Lindenblatt C.
      • Schulze-Osthoff K.
      • Totzke G.
      ). However, miR-124a is not detected in unstimulated HeLa cells (
      • Lim L.P.
      • Lau N.C.
      • Garrett-Engele P.
      • Grimson A.
      • Schelter J.M.
      • Castle J.
      • Bartel D.P.
      • Linsley P.S.
      • Johnson J.M.
      ). Furthermore, the facts that an unrelated mutation in the same stem also impairs translational silencing (SL3b in Fig. 6C), and that a compensatory mutation that restores the stem-loop structure but not the miR-124a seed region also restores translational silencing (SL3c in Fig. 6C) demonstrate that the TSE functions independently of miR-124a.
      IL-1 appears to activate translation of IκBζ by impairing the function of a strong silencing element that minimizes synthesis of IκBζ protein in unstimulated cells. This might be a way to prevent deleterious consequences of IκBζ function as reflected by induction of apoptosis when overexpressed (
      • Yamazaki S.
      • Muta T.
      • Takeshige K.
      ,
      • Totzke G.
      • Essmann F.
      • Pohlmann S.
      • Lindenblatt C.
      • Jänicke R.U.
      • Schulze-Osthoff K.
      ). How IL-1 interferes with the silencing mechanism remains to be elucidated. Our information on the mechanism of silencing itself is limited as well. Initiation is considered the rate-limiting step in translation, and often it is this part of the process and the factors involved in it that are targeted by regulatory mechanisms (
      • Gebauer F.
      • Hentze M.W.
      ). Important for efficient initiation of translation is the interaction of the cap-binding protein eIF4E with the scaffolding protein eIF4G that also binds PABP (poly(A)-binding protein). All three proteins can be targets of inhibitory factors. PABP facilitates translation by stimulating recruitment of 40 S and joining of 60 S ribosomal subunits (
      • Kahvejian A.
      • Svitkin Y.V.
      • Sukarieh R.
      • M'Boutchou M.N.
      • Sonenberg N.
      ). Its function can be inhibited (e.g. by the PABP-interacting protein PAIP2) (
      • Khaleghpour K.
      • Svitkin Y.V.
      • Craig A.W.
      • DeMaria C.T.
      • Deo R.C.
      • Burley S.K.
      • Sonenberg N.
      ). Silencing of Drosophila msl-2 mRNA via its 3′ UTR is exerted by binding of SXL, which recruits UNR, a protein that in turn interacts with PABP (
      • Duncan K.E.
      • Strein C.
      • Hentze M.W.
      ). A mechanism directly targeting PABP is unlikely to explain silencing by the IκBζ TSE because its function and sensitivity to IL-1 are maintained in a transcript that harbors a histone stem-loop instead of a poly(A) tail at its 3′ end (Fig. 8C). Histone stem-loops take part in circularizing mRNAs by interacting with eIF4G through SLBP and SLIP instead of PABP (
      • Marzluff W.F.
      • Wagner E.J.
      • Duronio R.J.
      ).
      Our observation that the IκBζ TSE does not silence polio virus IRES-dependent translation (Fig. 8A) argues against the involvement of mechanisms like that inhibiting translation of 15-lipoxygenase during early erythroid differentiation at a late step in initiation, recruitment of the 60 S ribosomal subunit (
      • Ostareck D.H.
      • Ostareck-Lederer A.
      • Shatsky I.N.
      • Hentze M.W.
      ,
      • Ostareck D.H.
      • Ostareck-Lederer A.
      • Wilm M.
      • Thiele B.J.
      • Mann M.
      • Hentze M.W.
      ). Because the polio virus IRES binds specifically to eIF4G (
      • de Breyne S.
      • Yu Y.
      • Unbehaun A.
      • Pestova T.V.
      • Hellen C.U.
      ), our result is in accordance with a cap-dependent mechanism, affecting an early step in translation like eIF4E binding or its interaction with eIF4G. A prominent example for this type of translational regulation is the masking of eIF4E by Maskin, which associates with the CPEB protein that binds the cytoplasmic polyadenylation element of maternal mRNAs (
      • Groisman I.
      • Jung M.Y.
      • Sarkissian M.
      • Cao Q.
      • Richter J.D.
      ), a crucial step in the regulation of translation of maternal mRNAs during oogenesis and early development. Similarly, during development of the anterior-posterior axis in Drosophila, the Smaug protein binds nanos mRNA and represses its translation via a block in eIF4G recruitment by the Smaug-interacting protein Cup, which, like Maskin, acts as an eIF4E-binding protein (
      • Nelson M.R.
      • Leidal A.M.
      • Smibert C.A.
      ).
      Initial attempts to identify the signal transduction pathway involved in IL-1-induced translational activation and stabilization argue against involvement of the p38 MAPK pathway, which is known to cause stabilization of numerous ARE-containing mRNAs (e.g. see Ref.
      • Frevel M.A.
      • Bakheet T.
      • Silva A.M.
      • Hissong J.G.
      • Khabar K.S.
      • Williams B.R.
      ). The lack of effect when expressing the MAPK kinase kinase MEKK1 (supplemental Fig. S3B) confirms this notion and suggests that JNK and NF-κB pathways, which are strongly activated as well, are also dispensable. Inhibitors of p38 MAPK, JNK, PI3K, and MKK1 did not have a significant effect on translational activation by IL-1 (not shown). Because IRAK1 and -2, which function more upstream in IL-1 signaling, appear to be involved in translational activation (Fig. 4, B and C), the relevant signaling pathway apparently diverges downstream of IRAKs. This is reminiscent of IL-1-induced signaling that causes stabilization of certain mRNAs (e.g. Gro3) independently of p38 MAPK by an as yet unidentified pathway (
      • Hartupee J.
      • Li X.
      • Hamilton T.
      ,
      • Tebo J.
      • Der S.
      • Frevel M.
      • Khabar K.S.
      • Williams B.R.
      • Hamilton T.A.
      ). Interestingly, IL-17 has been found to trigger stabilization of these mRNAs as well (
      • Hartupee J.
      • Liu C.
      • Novotny M.
      • Sun D.
      • Li X.
      • Hamilton T.A.
      ,
      • Hartupee J.
      • Liu C.
      • Novotny M.
      • Li X.
      • Hamilton T.
      ). In support of a common signaling pathway involved in stabilization and the translational activation reported here, IL-17, like IL-1, alleviates suppression of luciferase activity by the IκBζ TSE (not shown).
      Selective enhancement of translation of a distinct set of mRNAs in response to IL-1 is likely to contribute to the changes in gene expression induced by this proinflammatory cytokine. There is no apparent sequence homology among the members of this group that would explain their common regulation by IL-1. However, it is noteworthy that two of the mRNAs affected by this type of regulation encode members of the CCCH-type zinc finger proteins, and two others encode members of the IκB family. IκBζ has been shown to support expression of a set of genes, including that of IL-6 (
      • Kitamura H.
      • Kanehira K.
      • Okita K.
      • Morimatsu M.
      • Saito M.
      ,
      • Yamamoto M.
      • Yamazaki S.
      • Uematsu S.
      • Sato S.
      • Hemmi H.
      • Hoshino K.
      • Kaisho T.
      • Kuwata H.
      • Takeuchi O.
      • Takeshige K.
      • Saitoh T.
      • Yamaoka S.
      • Yamamoto N.
      • Yamamoto S.
      • Muta T.
      • Takeda K.
      • Akira S.
      ), whereas IκBδ counteracts IL-6 expression (
      • Kuwata H.
      • Matsumoto M.
      • Atarashi K.
      • Morishita H.
      • Hirotani T.
      • Koga R.
      • Takeda K.
      ,
      • Hirotani T.
      • Lee P.Y.
      • Kuwata H.
      • Yamamoto M.
      • Matsumoto M.
      • Kawase I.
      • Akira S.
      • Takeda K.
      ). IL-6 mRNA itself is among the transcripts with increased ribosome association following IL-1 exposure. The CCCH zinc finger protein ZC3H12A, whose mRNA is also affected by IL-1, has been reported to suppress expression of several inflammatory proteins, including IL-6, and NF-κB-dependent luciferase expression (
      • Liang J.
      • Wang J.
      • Azfer A.
      • Song W.
      • Tromp G.
      • Kolattukudy P.E.
      • Fu M.
      ) and recently to be involved in degradation of IL-6 mRNA (
      • Matsushita K.
      • Takeuchi O.
      • Standley D.M.
      • Kumagai Y.
      • Kawagoe T.
      • Miyake T.
      • Satoh T.
      • Kato H.
      • Tsujimura T.
      • Nakamura H.
      • Akira S.
      ). Cells of mice deficient in ZC3H12A show increased IL-6 expression (
      • Matsushita K.
      • Takeuchi O.
      • Standley D.M.
      • Kumagai Y.
      • Kawagoe T.
      • Miyake T.
      • Satoh T.
      • Kato H.
      • Tsujimura T.
      • Nakamura H.
      • Akira S.
      ). Thus, in addition to IL-6 itself, three other mRNAs are translationally activated that modify IL-6 expression. This suggests that translational activation by IL-1 has a profound influence on the course of IL-6 formation in inflammatory processes.
      Like ZC3H12A, RC3H1 (also named roquin) is a CCCH-type zinc finger protein. It contains a RING finger domain typical for ubiquitin ligases and was reported to limit expression of the T cell co-stimulatory receptor Icos by promoting degradation of its mRNA (
      • Yu D.
      • Tan A.H.
      • Hu X.
      • Athanasopoulos V.
      • Simpson N.
      • Silva D.G.
      • Hutloff A.
      • Giles K.M.
      • Leedman P.J.
      • Lam K.P.
      • Goodnow C.C.
      • Vinuesa C.G.
      ). Mutation of the Rc3h1 gene can lead to autoimmunity (
      • Vinuesa C.G.
      • Cook M.C.
      • Angelucci C.
      • Athanasopoulos V.
      • Rui L.
      • Hill K.M.
      • Yu D.
      • Domaschenz H.
      • Whittle B.
      • Lambe T.
      • Roberts I.S.
      • Copley R.R.
      • Bell J.I.
      • Cornall R.J.
      • Goodnow C.C.
      ).
      It has to be noted that due to technical constraints (e.g. one time point of IL-1 induction, a selection of fractions, selected conditions of separation (time/speed of centrifugation, density profile of the gradient)), additional mRNA targets might have been missed. Because some of the mRNAs strongly induced by IL-1 are expressed in non-stimulated cells only at very low levels, hampering their detection on oligonucleotide arrays, important additional mRNA candidates for translational activation by IL-1 could not be evaluated (including, for example, IL-1α itself and IL-1β, which was suggested to be translationally controlled) (
      • Schindler R.
      • Clark B.D.
      • Dinarello C.A.
      ,
      • Kaspar R.L.
      • Gehrke L.
      ).
      Several examples of translational control of inflammatory gene expression have been reported (
      • Piecyk M.
      • Wax S.
      • Beck A.R.
      • Kedersha N.
      • Gupta M.
      • Maritim B.
      • Chen S.
      • Gueydan C.
      • Kruys V.
      • Streuli M.
      • Anderson P.
      ,
      • Kotlyarov A.
      • Neininger A.
      • Schubert C.
      • Eckert R.
      • Birchmeier C.
      • Volk H.D.
      • Gaestel M.
      ). Activation of translation of negative regulators by IL-1 (Table 1) may achieve the same goal, eventual termination of the response, as IFN-γ-induced inhibition of translation; IFN-γ, which itself is translationally controlled by a PKR-activating sequence spanning part of its 5′ UTR and coding sequences (
      • Cohen-Chalamish S.
      • Hasson A.
      • Weinberg D.
      • Namer L.S.
      • Banai Y.
      • Osman F.
      • Kaempfer R.
      ,
      • Ben-Asouli Y.
      • Banai Y.
      • Pel-Or Y.
      • Shir A.
      • Kaempfer R.
      ), restricts translation of some of its target genes through a heteromeric complex assembled at the target mRNAs (
      • Mukhopadhyay R.
      • Jia J.
      • Arif A.
      • Ray P.S.
      • Fox P.L.
      ).
      We speculate that IL-1 activates a translational control mechanism that modulates expression of a group of genes, including IL-6, by increasing translation of their RNAs directly or through enhanced translation of factors controlling their transcription and mRNA stability. Identifying the signaling mechanism responsible for translational activation by IL-1 will be a crucial step in designing experiments to evaluate the impact of this control mechanism in a more physiological setting.

      Acknowledgments

      We thank Monika Barsch, Gesine Behrens, and Heike Schneider for technical assistance. We are grateful to Philip Cohen, Hansjoerg Hauser, Michael Martin, Detlef Neumann, and Mark Windheim for donating plasmids and to Matthias Gaestel for critically reviewing the manuscript.

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