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A protein‐directed riboswitch modulates translational repression of VEGF in response to hypoxia
Author(s) -
Fox Paul L,
Ray Partho S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.788.1
Subject(s) - translation (biology) , riboswitch , microbiology and biotechnology , rna , messenger rna , translational regulation , untranslated region , psychological repression , chemistry , protein biosynthesis , stress granule , rna binding protein , internal ribosome entry site , eukaryotic translation , ribonucleoprotein , biology , biochemistry , gene expression , non coding rna , gene
Riboswitches are found in bacteria, but similar switching mechanisms are rare in eukaryotic cells. We have shown vascular endothelial growth factor‐A (VEGF), a potent angiogenic factor produced by macrophages, is translationally silenced by the IFN‐gamma‐activated inhibitor of translation (GAIT) pathway. Translation is repressed by binding of the GAIT complex to a structural RNA element (GAIT element) in the 3′UTR. Remarkably, cell exposure to hypoxia specifically abrogates GAIT‐mediated translational repression of VEGF mRNA. The GAIT element is within the previously identified hypoxia stability region (HSR) in the VEGF 3′UTR which binds heterogenous nuclear ribonucleoprotein L (hnRNP L) during hypoxia and stabilizes the mRNA. RNA secondary structure prediction indicates the HSR might exist as two alternative conformers, only one of which permits formation of the GAIT structural element. We show binding of hnRNP L switches the HSR to the translation‐permissive conformer that does not bind the GAIT complex, and permits translation of VEGF mRNA even in the presence of IFN‐gamma. During normoxia, IFN reduces the level of hnRNP L, permitting the HSR to switch to the translation‐repressive conformer that allows GAIT complex binding. Our results describe a unique hypoxia‐responsive, protein‐directed riboswitch that regulates macrophage VEGF expression. Supported by NIH grants P01 HL29582 and P01 HL76491.