Transcription and translation get together

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Coupling transcription and translation via internal ribosome entry sites (IRES) in the insulin-like receptor gene (InR) allows Drosophila to rapidly adapt to changes in nutrient availability.

Eukaryotes have evolved sophisticated mechanisms to fine tune gene and protein expression, but this complexity can come with a cost: the more regulatory steps involved the less rapid will be the response to any environmental cue. Robert Tjian and colleagues now show that, in Drosophila melanogaster, transcription and translation can be coupled, by using internal ribosome entry sites (IRESs), to guarantee a rapid response to a lack of nutrients.

The authors studied the highly conserved INR–IGF (insulin-like receptor–insulin-like growth factor) pathway that has a central role in regulating metabolic homeostasis and organ size. In the presence of nutrients, INR activity drives cells towards growth and proliferation, triggering a signalling cascade that leads to the stimulation of protein translation by inactivating the translation initiation inhibitor 4E-BP (also known as THOR). Conversely, in the absence of nutrients, 4E-BP is active and binds the 7-methyl-guanosine (m7G) cap-binding protein Eukaryotic initiation factor 4E (eIF-4E), preventing the cap-dependent translation of most cellular mRNAs.

The authors had previously shown that under low-nutrient conditions InR is upregulated through a transcriptional feedback loop, mediated by the transcription factor forkhead box, subgroup O (FOXO). In the new study, they took a closer look at the InR gene structure and found that three promoters regulate InR expression, producing three transcripts that are expressed according to nutrient availability during each developmental stage. Interestingly, each transcript is characterized by a unique and unusually long 5' UTR.

The finding that InR is not only transcriptionally upregulated but also actively translated, as shown by increased protein synthesis in the presence of radiolabelled amino acids, under conditions in which 4E-BP maintains a global downregulation of translation, prompted the authors to investigate whether the long 5' UTRs could engage the translational machinery in an unconventional, cap-independent manner. Indeed, they found IRESs in the long InR 5' UTRs that allow, both in vitro and in vivo, eIF-4E-independent INR protein synthesis. Therefore they propose that coupling INR transcription and translation, which is further facilitated by the availability of the translation machinery because of 4E-BP global inhibition of translation, is a mechanism to amplify the INR signalling pathway as soon as nutrients become available.

Beyond adding new insights into the regulation of the INR–IGF pathway, this work provides new evidence for the role of cellular IRESs in a physiological response.

Francesca Pentimalli

References

Marr, M. T., D'Alessio, J. A., Puig, O. & Tjian, R. IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback. Genes Dev. 21, 175–183 (2007) | Article | PubMed |