Researchers uncover key cell signal that triggers tissue response to amino acid insufficiency
Their new finding, published in Science, overturns a longstanding hypothesis regarding this physiologically important process.
Amino acids play an essential role in many processes in the human body. When the body doesn’t get enough of these essential building blocks of protein, early warning signals are activated that help cells correct this nutritional shortfall. Activation of these signals impacts cell survival and can also have wide-ranging effects on chronic inflammation, wound healing, and lifespan. Understanding how amino acid insufficiency initiates these signals can lead to new approaches to therapeutic regulation of human disease.
The authors of a recent study published in Science examined the role of GCN2, a key signaling protein that is activated when amino acid levels start to fall below the levels required for efficient protein synthesis. Prior work has generated multiple hypotheses for how this activation might happen, but researchers from Harvard School of Dental Medicine (HSDM) and Harvard Medical School developed a new experimental system that allowed them to test the connections that link stress-induced changes in the cell's protein synthesis machinery to the activation of GCN2.
“We knew that deciphering GCN2 activation was the key to understanding a cell’s response to amino acid stress, including how the limitation of amino acid availability can have therapeutic or life-extending effects,” said author Tracy Keller, instructor in HSDM’s Department of Developmental Biology.
One result of stresses that interrupt protein synthesis is that ribosomes, the cell’s protein-making machines, can stall while translating an mRNA, thereby inducing collisions with trailing ribosomes on that same message. The researchers found that these ribosome collisions are critical signals for initiating the cellular response to amino acid shortfall.
When the ribosomes collide with each other, a sensor protein called GCN1 detects the collision, which in turn allows GCN2 to attach to the ribosomes and switch on the cell’s stress response.
“This mechanistic study defines the core requirements of GCN2’s activation, coupling GCN2 activation to ribosomal state,” said Keller. “This new understanding of how the mechanism works will allow scientists to take this finding further and study how this could lead to potential therapeutic interventions.”
An important tool that enabled the researchers to mimic amino acid insufficiency in their study was the use of halofuginone (HF), a semi-synthetic drug derived from a root used as an herbal therapy in traditional Chinese medicine. In 2012, the Whitman Lab established that HF acts to inhibit an enzyme that is essential for the incorporation of proline into a protein. HF has been found to have a wide range of potential therapeutic benefits, including the suppression of chronic inflammation and fibrosis, promotion of resolution of non-healing wounds, and extension of lifespan in mice.
“These observations highlight the importance of understanding how amino acid stress is linked to the activation of signals that might account for these beneficial effects. The discovery of the cellular target of this traditional herbal remedy brought insight and attention to the therapeutic benefits of amino acid restriction, and provided a critical tool for querying GCN2’s mechanism of activation,” said Malcolm Whitman, professor of Developmental Biology and co-author of the paper.
This work was supported by the National Institutes of Health, the Packard Foundation, and internal HSDM funds.