HuR/ELAVL1 RNA binding protein modulates interleukin-8 induction by muco-active ribotoxin deoxynivalenol.
HuR/Elav-like RNA binding protein 1 (ELAVL1) positively regulates mRNA stability of AU-rich elements (ARE)-containing transcript such as pro-inflammatory cytokines. Ribotoxic stresses can trigger the production of pro-inflammatory mediators by enhancing mRNA stability and the transcriptional activity. We investigated the effects of ribotoxin deoxynivalenol (DON) on HuR translocation and its involvement in the regulation of the pro-inflammatory interleukin-8 (IL-8) mRNA stability. Exposure to the muco-active DON induced nuclear export of both endogenous and exogenous HuR RNA binding protein in human intestinal epithelial cells. Moreover, the interference with HuR protein production suppressed ribotoxic DON-induced IL-8 secretion and its mRNA stability. Cytoplasmic HuR protein interacted with IL-8 mRNA and the complex stabilization was due to the presence of 3'-untranslated region of the transcript. Partly in terms of IL-8-modulating transcription factors, HuR protein was demonstrated to be positively and negatively associated with DON-induced early growth response gene 1 (EGR-1) and activating transcription factor 3 (ATF3), respectively. HuR was a critical mechanistic link between ribotoxic stress and the pro-inflammatory cytokine production, and may have a broader functional significance with regard to mucosal insults since ribotoxic stress responses are also produced upon interactions with the diverse environment of gut.
Choi
Hye Jin
HJ
Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Yangsan, 626-813, Republic of Korea.
Yang
Hyun
H
Park
Seong Hwan
SH
Moon
Yuseok
Y
D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D014255:Trichothecenes / Q000633:toxicity*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016209:Interleukin-8; D016601:RNA-Binding Proteins; D014255:Trichothecenes; C007262:deoxynivalenol