Every living cell is no less than a party, with a team of highly trained Disc jockeys (DJs). When major events such as cell division or nutrient droughts happen, these molecular DJs create just the right mix of metabolites and proteins to ensure a seamless transition from one state to another. So, who are these cellular DJs, and how do they do this?
A team of researchers led by Sunil Laxman from the Institute of Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, have discovered a transfer RNA (tRNA) modification that calibrates the different metabolites in the cell to ensure optimal growth and proliferation.
Transfer RNAs (tRNAs) are the protagonists in translation—the process by which nucleic acid information is converted into strings of amino acids called proteins. Adding a feather to their cap, chemical modifications on these tRNA structures make them flexible to carry out a number of duties. Thiolation is one such modification that adds a sulphur molecule (a thiol) to the tRNA backbone at a specific location. Some studies have suggested that this modification might regulate metabolism and response to nutrients (amino acids), but the underlying mechanism is unknown.
Given that the cell has stalwart proteins such as target of rapamycin (TORs) and AMP-activated protein kinases (AMPKs) to sense nutrients and metabolites, why and how would a tRNA modulate a cell’s energy needs? This was the question the team set out to answer.
Ritu Gupta, the lead author of the paper, used the common baker’s yeast, for her investigations. By depleting cells of proteins that carry out this thiolation of tRNAs, Ritu unexpectedly observed that thiolation-deficient yeast cells built-up amino acid stores, but still behaved as if they were starved of amino acids. In cellular terms, these cells were directing their efforts away from making nucleotides (which is a hallmark of growing and dividing cells).
What surprised her further was the following observation. The cells without thiolation appeared starved even though there was no starvation, and instead of burning their available carbon resources for energy, were instead storing them away as a stash of trehalose! Grappling with this paradox, the team decided to profile the global changes in RNA and ribosomes to see what tRNA thiolation did in the cells.
“We analyzed the data from the genome-wide analysis and were very positive about finding something very obvious in it. But turns out after the analysis, we were still as clueless as we were before!” exclaimed Ritu.
However, upon closer look, the researchers noticed that a group of unassuming genes that were involved in maintaining levels of phosphates had very low amounts in the cells lacking thiolation. This observation suggested that the thiolation-less cells had engineered phosphate starvation.
On a blackboard, the team drew up all the biochemical reactions that brought together carbon, nitrogen, and phosphate utilization within the cell. Hidden away in this intricate network of carbon metabolism was a route of trehalose synthesis, which in fact revitalized cells with phosphate. They realized that the thiolation-deficient yeast cells were directing carbon resources to trehalose, so that they could make up for the loss of phosphate.
Think now of the thiolation of certain tRNAs, as DJs within these cells. The thiolated tRNAs actually help cells to tune responses to overall nutrient (amino acid) presence. To do that, they ‘scratch’ phosphates, making a handle to control and mix up the big metabolism players, carbon and nitrogen. By doing this, the cells can integrate all this information for cellular growth.
But why tRNAs? “Using a tRNA modification, something so intimately coupled to how cells make proteins, to regulate metabolism is a very effective way for cells to tune growth, depending on the nutrients available,” says Sunil, who is excited to take this study forward. Since this study conceptually addresses how genetically identical cells can exhibit different properties, it has implications for our understanding of how tumors develop, and how microbes might switch to more pathogenic states.
A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis. Ritu Gupta, Adhish Walvekar, Shun Liang, Zeenat Rashida, Premal Shah, Sunil Laxman. eLife. July 2019, 8:e44795