HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization

• Published in: The Journal of immunology (1950) Vol. 191; no. 2; pp. 640 - 649
• Main Authors: Herjan, Tomasz, Yao, Peng, Qian, Wen, Li, Xiao, Liu, Caini, Bulek, Katarzyna, Sun, Dongxu, Yang, Wen-Pin, Zhu, Jun, He, Aiqing, Carman, Julie A, Erzurum, Serpil C, Lipshitz, Howard D, Fox, Paul L, Hamilton, Thomas A, Li, Xiaoxia
• Format: Journal Article
• Language: English
• Published: United States 15-07-2013
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Line; Chemokine CXCL1 - genetics; Chemokine CXCL5 - genetics; ELAV Proteins - genetics; ELAV Proteins - metabolism; HeLa Cells; Humans; Inflammation - immunology; Interleukin-17 - metabolism; Lung - metabolism; Mice; Mice, Knockout; Protein Binding; Respiratory Mucosa - metabolism; RNA Stability; RNA, Messenger - metabolism; Signal Transduction; Ubiquitination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1203315

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.