doi:10.1038/nindia.2008.338 Published online 21 December 2008
What does a cell do in a dilemma, especially when the dilemma is between survival and causing tissue injury? A new study describes a novel molecular mechanism of resolving such a dilemma by which a monocytic cell integrates the responses to two opposing stimuli — inflammation and hypoxia — thereby regulating the synthesis of vascular endothelial growth factor (VEGF-A)1.
Monocytes are precursors of macrophages, the cells that constitute the first line of defence of the body by mounting the inflammatory response against invading micro-organisms or damaged cells. The interferon-γ-activated inhibitor of translation (GAIT) complex is a multi-protein complex that inhibits the translation of multiple inflammatory genes in macrophages, in response to the cytokine interferon-γ thereby preventing build-up of harmful inflammatory proteins.
One of the GAIT complex targets is VEGF-A, the major angiogenic protein produced by macrophages that regulates blood vessel development in various inflammatory conditions. The GAIT complex binds to a RNA stem-loop element (GAIT element) in the 3'-untranslated region of the VEGF-A mRNA and represses its translation. However, continued expression of VEGF-A is required to relieve tissue hypoxia, and allow cell survival in conditions where inflammation coexists with hypoxia, such as in atherosclerotic plaques and tumors.
This study shows how the cell resolves this dilemma: hypoxia overcomes the translation repression of VEGF-A by causing a binary conformational change in the structure of the GAIT element. The structural change is dictated by mutually exclusive, stimulus-dependent binding of proteins, namely, the GAIT complex and heterogeneous nuclear ribonucleoprotein L (hnRNP L).
The VEGF-A RNA switch may represent the founding member of a family of protein-dependent RNA switches that evolved to regulate gene expression in multicellular animals in which the precise integration of disparate, sometimes antagonistic, inputs are necessary for survival.