An Essential Function of the SRC-3 Coactivator in Suppression of Cytokine MRNA Translation and Inflammatory Response

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2007 Mar 14

PMID 17349961

Citations 81

Authors

Chundong Yu

Brian York

Shu Wang

Qin Feng

Jianming Xu

Bert W OMalley

Affiliations

Soon will be listed here.

Abstract

Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator for nuclear receptors and other transcription factors. Although multiple physiological roles of SRC-3 have been revealed, its involvement in the inflammatory process remains unclear. Herein we show that SRC-3(-/-) mice are markedly hypersensitive to LPS-induced endotoxic shock. In response to LPS, SRC-3(-/-) macrophages produce significantly more proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta than wild-type controls, although they express similar amounts of cytokine mRNAs, suggesting that SRC-3 can exert effects at translational levels. Increased heavy polysome-associated TNF-alpha and IL-1beta mRNAs in SRC-3(-/-) macrophages implicate SRC-3 as a translational repressor. SRC-3 may cooperate with other translational repressors such as TIA-1 and TIAR to regulate cytokine mRNA translation. Collectively, our studies reveal an essential function of SRC-3 as a coordinator of inflammatory mRNA translation and as a physiologic protective factor against the lethal endotoxic shock triggered by an acute inflammatory response.

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References

Wu R, Qin J, Yi P, Wong J, Tsai S, Tsai M . Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell. 2004; 15(6):937-49. DOI: 10.1016/j.molcel.2004.08.019. View

Tian Q, Streuli M, Saito H, Schlossman S, Anderson P . A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell. 1991; 67(3):629-39. DOI: 10.1016/0092-8674(91)90536-8. View

Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember L . Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell. 2004; 15(12):5383-98. PMC: 532018. DOI: 10.1091/mbc.e04-08-0715. View

Coste A, Antal M, Chan S, Kastner P, Mark M, OMalley B . Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J. 2006; 25(11):2453-64. PMC: 1478181. DOI: 10.1038/sj.emboj.7601106. View

Galanos C, Freudenberg M, REUTTER W . Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci U S A. 1979; 76(11):5939-43. PMC: 411768. DOI: 10.1073/pnas.76.11.5939. View

Reily M, Pantoja C, Hu X, Chinenov Y, Rogatsky I . The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. EMBO J. 2005; 25(1):108-17. PMC: 1356362. DOI: 10.1038/sj.emboj.7600919. View

Morikawa A, Sugiyama T, Kato Y, Koide N, Jiang G, Takahashi K . Apoptotic cell death in the response of D-galactosamine-sensitized mice to lipopolysaccharide as an experimental endotoxic shock model. Infect Immun. 1996; 64(3):734-8. PMC: 173830. DOI: 10.1128/iai.64.3.734-738.1996. View

Hawes A, Rock C, Keogh C, Lowry S, Calvano S . In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. Infect Immun. 1992; 60(7):2641-7. PMC: 257215. DOI: 10.1128/iai.60.7.2641-2647.1992. View

Katsanou V, Papadaki O, Milatos S, Blackshear P, Anderson P, Kollias G . HuR as a negative posttranscriptional modulator in inflammation. Mol Cell. 2005; 19(6):777-89. DOI: 10.1016/j.molcel.2005.08.007. View

10.

Garnon J, Lachance C, Di Marco S, Hel Z, Marion D, Ruiz M . Fragile X-related protein FXR1P regulates proinflammatory cytokine tumor necrosis factor expression at the post-transcriptional level. J Biol Chem. 2004; 280(7):5750-63. DOI: 10.1074/jbc.M401988200. View

11.

Zhang W, Wagner B, Ehrenman K, Schaefer A, DeMaria C, Crater D . Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Mol Cell Biol. 1993; 13(12):7652-65. PMC: 364837. DOI: 10.1128/mcb.13.12.7652-7665.1993. View

12.

Chen H, Lin R, Schiltz R, Chakravarti D, Nash A, Nagy L . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997; 90(3):569-80. DOI: 10.1016/s0092-8674(00)80516-4. View

13.

Gueydan C, Droogmans L, Chalon P, Huez G, Caput D, Kruys V . Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. J Biol Chem. 1999; 274(4):2322-6. DOI: 10.1074/jbc.274.4.2322. View

14.

Li W, Simarro M, Kedersha N, Anderson P . FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression. Mol Cell Biol. 2004; 24(24):10718-32. PMC: 533970. DOI: 10.1128/MCB.24.24.10718-10732.2004. View

15.

Chinetti G, Fruchart J, Staels B . Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000; 49(10):497-505. DOI: 10.1007/s000110050622. View

16.

Carballo E, Lai W, Blackshear P . Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998; 281(5379):1001-5. DOI: 10.1126/science.281.5379.1001. View

17.

Wu R, Qin J, Hashimoto Y, Wong J, Xu J, Tsai S . Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Mol Cell Biol. 2002; 22(10):3549-61. PMC: 133790. DOI: 10.1128/MCB.22.10.3549-3561.2002. View

18.

Torres-Arzayus M, Font de Mora J, Yuan J, Vazquez F, Bronson R, Rue M . High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell. 2004; 6(3):263-74. DOI: 10.1016/j.ccr.2004.06.027. View

19.

Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S . Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators. J Biol Chem. 2000; 275(43):33201-4. DOI: 10.1074/jbc.C000517200. View

20.

Stoecklin G, Colombi M, Raineri I, Leuenberger S, Mallaun M, Schmidlin M . Functional cloning of BRF1, a regulator of ARE-dependent mRNA turnover. EMBO J. 2002; 21(17):4709-18. PMC: 126184. DOI: 10.1093/emboj/cdf444. View