To Turn On or Turn Off: One Molecule’s Dilemma?

Science's STKE  20 Mar 2007:
Vol. 2007, Issue 378, pp. tw92
DOI: 10.1126/stke.3782007tw92

Steroid receptor coactivator-3 (SRC-3) is a member of the SRC family of nuclear receptor coactivators and is known for its function as an enhancer of gene transcription. Although knockout studies show roles for SRC-3 in development, oncogenesis, and tumor suppression, little is known about its contribution to immune responses. In this study, Yu et al. first demonstrated that SRC-3−/− mice were more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock than were wild-type mice. The authors found increased concentrations of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the sera of SRC-3−/− animals. Peritoneal macrophages from SRC-3−/− mice secreted more of these cytokines after treatment with LPS than did macrophages from wild-type mice. These effects were not observed in macrophages from SRC-1−/− or SRC-2−/− mice. Electrophoretic mobility shift assays revealed that LPS-induced activation of the transcription factor NF-κB was comparable in wild-type and SRC-3−/− cells, ruling out a role for SRC-3 in repressing NF-κB activation. There were no differences in the abundance or half-lives of proinflammatory cytokine mRNAs when comparing wild-type and SRC-3−/−macrophages, nor were there any differences in the secretion or stability of TNF-α. Polysomal profile analysis, which estimates the proportion of actively translating cytoplasmic mRNAs, revealed that the increased production of TNF-α and IL-1β by SRC-3−/− macrophages was due to enhanced translation. SRC-3, which does not contain RNA-binding motifs, associated with the translational repressors TIA-1 and TIAR, providing a mechanism by which SRC-3 may repress mRNA translation. This study suggests that a coregulator protein can act as a transcriptional coactivator or a translational corepressor, depending on the cellular context.

C. Yu, B. York, S. Wang, Q. Feng, J. Xu, B. W. O’Malley, An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response. Mol. Cell 25, 765-778 (2007). [PubMed]