Insulin regulates translation

By controlling how many ribosomes coat a certain mRNA in C. elegans, intracellular insulin signaling can regulate how many copies of a protein are made, and how quickly, giving cells more flexibility when responding to changes in the environment.

C. elegans
Image: Wikimedia commons,
Bob Goldstein, UNC Chapel Hill

The results, published, in the September 8th issue of Cell Metabolism, hold implications for a range of fields, including aging and diabetes, in which insulin signaling is known to play a role. "We have found a new way in which insulin controls the proteins that are made, and some of those proteins are really important for the survival of the worms," said lead author linkurl:Gordon Lithgow,;http://www.buckinstitute.org/TheScience/thelithgow/ of the Buck Institute for Age Research. "That throws up questions as to whether insulin is doing the same in humans and that presents a whole new set of targets for potential therapies or interventions in both aging and diabetes." Insulin-like signaling -- which can be activated by either the insulin receptor or other insulin-like receptors -- has previously been identified as an important player in its aging, stress response and longevity in C. elegans, in addition to its normal role as a metabolism regulator. Insulin is traditionally thought to regulate protein expression through changes to the number of mRNA copies made from a gene -- regulation on the level of transcription -- not in changes to the number of proteins made from the mRNA. Now, Lithgow and his colleagues present evidence that insulin may also regulate gene expression at this other level -- the level of translation. "It's a really in-depth study, going beyond the genetics and really getting into mechanisms [of insulin action]," said linkurl:Heidi Tissenbaum,;http://www.umassmed.edu/pgfe/faculty/tissenbaum.cfm a molecular geneticist studying insulin-like signaling and aging at the University of Massachusetts Medical School, who was not involved in the study. "It's a very solid paper, and it's really pushing our understanding a little bit and opening up new possibilities [for the study of aging]." Lithgow's team found this special regulatory role by studying worms which have lowered insulin signaling because they are missing the gene for an insulin-like receptor. These worms were better able to tolerate the stress of being exposed to higher temperatures, also called heat shock, and thus lived much longer than their normal brethren. Treating the worms with a drug that blocked transcription of new genes, the team saw no changes in their ability to survive the stress of a heat shock, suggesting that insulin signaling action were affecting another part of the gene-to-protein pathway. The researchers then turned to the possibility of translational regulation. They harvested all of the mRNA from the worms in a way that preserved its connections with the cell's protein-making equipment, called ribosomes. Then, knowing that many ribosomes can attach to an mRNA transcript at the same time and make multiple copies of the protein simultaneously, they separated the mRNAs by the number of appended ribosomes. Comparing normal and mutant insulin signaling worms under heat-stress conditions, the team found 59 genes that differed significantly in the ribosome binding patterns -- and thus also the rate of protein production. "Each of these genes is a new story and each of those genes may have metabolic consequences, may have effects on stress resistance, and may have an effect on aging," said Lithgow. What's interesting about regulation of protein expression at the translational level is that it can induce effects much more quickly than changes in gene expression can, added second author linkurl:Aric Rogers;http://www.buckinstitute.org/Labs/KapahiLab/labMembers.asp of Buck Institute for Age Research. "Modulating translation is a much faster way of regulating gene expression than transcription," said Rodgers, "Translation is right at the point of protein synthesis. If you change that quickly you can much more quickly respond to an environmental change or insult." "This paper is breaking new ground and used novel techniques to do it," said linkurl:William Sonntag,;http://www.ouhsc.edu/geriatricmedicine/roca/Research/sonntag.html a neuroendocrinologist studying age-related brain function at the University of Oklahoma Health Sciences Center, who was not involved in the study. "I think this gives a new avenue for the research, that there really are alternative pathways [to regulate protein levels]." Stay tuned to The Scientist.com, where we'll be delving into the many non-metabolic roles of insulin in our October issue. G. McColl, et al., "Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans," Cell Metabolism, 12: 260-72, 2010.
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[30th June 2005]