MKP-1 regulates cytokine mRNA stability through selectively modulation subcellular translocation of AUF1

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• 作者：Hong Yu^a ; Yuhao Sun^a ; Courtney Haycraft^a ;   ; ^b ; Viswanathan Palanisamy^a ; Keith L. Kirkwood^a ;   ; ^c ;   ; ^{klkirk@musc.edu}
• 关键词：MKP-1 ; AUF1 ; TTP ; Cytokine ; mRNA
• 刊名：Cytokine
• 出版年：2011
• 出版时间：November 2011
• 年：2011
• 卷：56
• 期：2
• 页码：245-255
• 全文大小：1501 K

文摘

MAPK phosphatase-1 (MKP-1)/dual specificity protein phosphatase-1 (DUSP-1) is a negative regulator of the host inflammatory response to infection. However, the mechanisms underlying the regulation of cytokine expression by MKP-1, especially at the post-transcriptional level, have not been fully delineated. In the current study, MKP-1 specifically dephosphorylated activated MAPK responses and attenuated LPS-induced IL-6, IL-10, and TNF-¦Á expression. In addition, MKP-1 was important in destabilizing cytokine mRNAs. In LPS-stimulated rat macrophages with overexpressed MKP-1, half-lives of IL-6, IL-10 and TNF-¦Á mRNAs were significantly reduced compared to controls. Conversely, half-lives of IL-6, IL-10, and TNF-¦Á mRNAs were significantly increased in bone marrow macrophages derived from MKP-1 knock out (KO) mice compared with macrophages derived from MKP-1 wild type (WT) mice. Furthermore, MKP-1 promoted translocation of RNA-binding protein (RNA-BP) ARE/poly-(U) binding degradation factor 1 (AUF1) from the nucleus to the cytoplasm in response to LPS stimulation as evidenced by Western blot and immunofluorescent staining. Knockdown AUF1 mRNA expression by AUF1 siRNA in MKP-1 WT bone marrow macrophages significantly delayed degradation of IL-6, IL-10 and TNF- ¦Á mRNAs compared with controls. Finally, AUF1 was immunoprecipitated with the RNA complex in cellular lysates derived from bone marrow macrophages of MKP-1 KO vs. WT mice, which had increased AUF1-bound target mRNAs, including IL-6, IL-10, and TNF-¦Á in WT macrophages compared with MKP-1 KO macrophages. Thus, this work provides new mechanistic insight of MKP-1 signaling and regulation of cytokine mRNA stability through RNA binding proteins in response to inflammatory stimuli.