ABSTRACT
Cells respond to a variety of cellular stresses, including DNA damage, by regulating genes whose expression modulates cell cycle arrest, DNA repair, senescence, and/or apoptosis. MicroRNAs (miRNAs) play essential roles in both normal development and disease pathogenesis by destabilizing mRNAs and inhibiting translation. In turn, miRNA biogenesis, turnover, and activity can be regulated by specific RNA-binding proteins. Here we show that Mex-3B, an hnRNP K homology (KH) domain-containing RNA-binding protein, critically modulates DNA stress-induced apoptosis by posttranscriptionally upregulating the pro-apoptotic BH3 (Bcl-2 homology region 3)-only family member Bim. Furthermore, our data indicate that binding of Mex-3B to the 3'-untranslated region (3'UTR) of Bim interferes with the interaction of an Argonaute (Ago)-miR-92a complex with a miR-92a target site present in the Bim RNA. Our results provide novel insights into the posttranscriptional mechanisms that are critical for cellular stress responses.
Subject(s)
3' Untranslated Regions/genetics , Apoptosis/genetics , Bcl-2-Like Protein 11/genetics , MicroRNAs/genetics , RNA-Binding Proteins/metabolism , Base Sequence , Cell Line, Tumor , DNA Damage , Gene Expression Regulation , Humans , Nucleic Acid Conformation , Tumor Suppressor Protein p53/metabolismABSTRACT
Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.
