title: HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization.
abstract: 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.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Herjan
authors.forename: Peng
authors.initials: P
authors.lastname: Yao
authors.forename: Wen
authors.initials: W
authors.lastname: Qian
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Dongxu
authors.initials: D
authors.lastname: Sun
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.forename: Julie A
authors.initials: JA
authors.lastname: Carman
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Howard D
authors.initials: HD
authors.lastname: Lipshitz
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hamilton
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000235:genetics*; D054365:Chemokine CXCL5 / Q000235:genetics*; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; C475895:Cxcl1 protein, mouse; C094739:Cxcl5 protein, mouse; D051959:ELAV Proteins; D020381:Interleukin-17; D012333:RNA, Messenger; C515963:Traf3ip2 protein, mouse