HuR Is Required for IL-17–Induced Act1-Mediated CXCL1 and CXCL5 mRNA Stabilization

IL-17, a major inflammatory cytokine plays a critical role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report a new function of RNA-binding protein HuR in IL-17–induced Act1-mediated chemokine mRNA stabilization. HuR deficiency markedly reduced IL-17–induced chemokine expression due to increased mRNA decay. Act1-mediated HuR polyubiquitination was required for the binding of HuR to CXCL1 mRNA, leading to mRNA stabilization. Although IL-17 induced the coshift of Act1 and HuR to the polysomal fractions in a sucrose gradient, HuR deficiency reduced the ratio of translation-active/translation-inactive IL-17–induced chemokine mRNAs. Furthermore, HuR deletion in distal lung epithelium attenuated IL-17–induced neutrophilia. In summary, HuR functions to couple receptor-proximal signaling to posttranscriptional machinery, contributing to IL-17–induced inflammation.

[1]  G. Shaw,et al.  Pillars article: a conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986. 46: 659-667. , 2012, Journal of immunology.

[2]  T. Hamilton,et al.  Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF) , 2011, Nature Immunology.

[3]  M. Chance,et al.  The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation , 2011, Nature Immunology.

[4]  E. Pietras,et al.  IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. , 2010, The Journal of clinical investigation.

[5]  R. Ransohoff,et al.  Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. , 2010, Immunity.

[6]  Zhijian J. Chen,et al.  Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling , 2009, Science Signaling.

[7]  S. Srikantan,et al.  Ubiquitin‐mediated proteolysis of HuR by heat shock , 2009, The EMBO journal.

[8]  S. Gaffen,et al.  Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis , 2009, The Journal of experimental medicine.

[9]  Zhijian J. Chen,et al.  Nonproteolytic functions of ubiquitin in cell signaling. , 2009, Molecular cell.

[10]  Zizhen Kang,et al.  The Critical Role of Epithelial-Derived Act1 in IL-17- and IL-25-Mediated Pulmonary Inflammation1 , 2009, The Journal of Immunology.

[11]  J. Whitsett,et al.  Conditional expression of genes in the respiratory epithelium in transgenic mice: cautionary notes and toward building a better mouse trap. , 2009, American journal of respiratory cell and molecular biology.

[12]  H. Lou,et al.  Diverse molecular functions of Hu proteins , 2008, Cellular and Molecular Life Sciences.

[13]  A. Blauvelt.  T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. , 2008, The Journal of investigative dermatology.

[14]  P. Anderson.  Post-transcriptional control of cytokine production , 2008, Nature Immunology.

[15]  Shyamasree Datta,et al.  Tristetraprolin Regulates CXCL1 (KC) mRNA Stability1 , 2008, The Journal of Immunology.

[16]  S. Gaffen,et al.  Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. , 2008, Cytokine.

[17]  T. Hamilton,et al.  IL-17 Enhances Chemokine Gene Expression through mRNA Stabilization1 , 2007, The Journal of Immunology.

[18]  V. Kuchroo,et al.  TH-17 cells in the circle of immunity and autoimmunity , 2007, Nature Immunology.

[19]  V. Tuohy,et al.  The adaptor Act1 is required for interleukin 17–dependent signaling associated with autoimmune and inflammatory disease , 2007, Nature Immunology.

[20]  Satoshi Tanaka,et al.  T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis , 2007, The Journal of experimental medicine.

[21]  C. Dong,et al.  Act1 Adaptor Protein Is an Immediate and Essential Signaling Component of Interleukin-17 Receptor* , 2006, Journal of Biological Chemistry.

[22]  J. Derry,et al.  Cutting Edge: Interleukin 17 Signals through a Heteromeric Receptor Complex , 2006, The Journal of Immunology.

[23]  Y. Iwakura,et al.  The IL-23/IL-17 axis in inflammation. , 2006, The Journal of clinical investigation.

[24]  R. Pardi,et al.  LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation1 , 2006, The Journal of Immunology.

[25]  Tom R. Mayo,et al.  ARE‐mRNA degradation requires the 5′–3′ decay pathway , 2006, EMBO reports.

[26]  Tala Bakheet,et al.  ARED 3.0: the large and diverse AU-rich transcriptome , 2005, Nucleic Acids Res..

[27]  L. Paillard,et al.  AU-rich elements and associated factors: are there unifying principles? , 2006, Nucleic acids research.

[28]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[29]  M. Fechir,et al.  Involvement of KSRP in the post-transcriptional regulation of human iNOS expression–complex interplay of KSRP with TTP and HuR , 2005, Nucleic acids research.

[30]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[31]  M. Gorospe,et al.  Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs , 2004, The EMBO journal.

[32]  T. Hla,et al.  The RNA-binding Protein HuR Regulates the Expression of Cyclooxygenase-2* , 2003, Journal of Biological Chemistry.

[33]  Roy Parker,et al.  Decapping and Decay of Messenger RNA Occur in Cytoplasmic Processing Bodies , 2003 .

[34]  Frank Eisenhaber,et al.  The STIR-domain superfamily in signal transduction, development and immunity. , 2003, Trends in biochemical sciences.

[35]  A. Andoh,et al.  Increased expression of interleukin 17 in inflammatory bowel disease , 2003, Gut.

[36]  I. Homma,et al.  Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. , 2002, Immunity.

[37]  M. Mann,et al.  AU Binding Proteins Recruit the Exosome to Degrade ARE-Containing mRNAs , 2001, Cell.

[38]  Q. Hamid,et al.  IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. , 2001, The Journal of allergy and clinical immunology.

[39]  J. Shellito,et al.  Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense , 2001, The Journal of experimental medicine.

[40]  J. A. Steitz,et al.  HuR and mRNA stability , 2001, Cellular and Molecular Life Sciences CMLS.

[41]  J. Steitz,et al.  Protein Ligands to Hur Modulate Its Interaction with Target Mrnas in Vivo , 2000, The Journal of cell biology.

[42]  X. Hua,et al.  Act1, an NF-κB-activating protein , 2000 .

[43]  K. Yamaguchi,et al.  Requirement of Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 in Interleukin 17 Signal Transduction , 2000, The Journal of experimental medicine.

[44]  G. Stark,et al.  Act1, an NF-kappa B-activating protein. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  G. M. Wilson,et al.  Regulation of AUF1 Expression via Conserved Alternatively Spliced Elements in the 3′ Untranslated Region , 1999, Molecular and Cellular Biology.

[46]  A. Shyu,et al.  RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein , 1998, The EMBO journal.

[47]  J. Banchereau,et al.  T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines , 1996, The Journal of experimental medicine.