Arginine is an amino acid that supports many essential functions throughout the body. It helps cells build proteins that carry out a wide range of biological processes. The body produces arginine naturally, and people also obtain it from many protein-rich foods. Abnormally low arginine levels have been linked to several diseases, including colon cancer.
Sohail Tavazoie, who leads Rockefeller University’s Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology, has spent years studying this connection. In 2023, his team reported that depriving colon cancer cells of arginine caused them to accumulate more mutations.
Their latest research shows that arginine deficiency may also weaken the immune system. When arginine is scarce, cells struggle to produce MHC-1, a protein that helps alert the immune system to threats such as mutated cells and invading viruses.
Arginine May Restore a Key Immune Signal
The researchers also found that a moderate amount of arginine, roughly equivalent to the quantity in a couple of over-the-counter tablets, could potentially restore expression of the genes involved in MHC-1 production. The findings were published in Cell.
“Our work reveals how a lack of arginine interferes with the immune system, and suggests that upping arginine intake could prove beneficial,” says first author Qiushuang Wu, a postdoc in the lab. “Perhaps that means it could be used in combination with other therapies to treat both cancer and viral infections.”
“Arginine supplementation could be readily tested in patients receiving immunotherapies or given to high-risk populations exposed to viral pathogens,” Tavazoie suggests. “Considering that arginine is inexpensive and readily available, we hope that therapeutic and preventative studies could be undertaken soon.”
How Codons Guide Protein Production
Amino acids are commonly described as the building blocks of proteins. Their production is directed by codons, groups of three DNA bases that provide cellular instructions for making individual amino acids. Six different codons encode arginine, highlighting its broad importance in protein production.
Scientists already know that changes in amino acid availability can affect cellular metabolism and signaling. Far less is understood about whether those changes can directly influence gene expression.
For the new study, Wu examined whether shifts in arginine levels caused by diet or disease could alter gene expression. The work was supported in part by the Stavros Niarchos Foundation (SNF) Institute for Global Infectious Disease Research at The Rockefeller University and the Weill Cancer East Hub.
The researchers studied several disease models, including colon cancer, influenza, and SARS-CoV-2. Each of these conditions has previously been associated with unusual levels of different amino acids.
“One of the most dramatic patterns to emerge was that arginine was the most depleted amino acid in all of these diseases,” she says.
Low Arginine Disrupts Immune Recognition
Wu used cell cultures to identify genes and proteins affected by declining arginine levels. She found that 414 proteins were present at unusually low levels. Most were produced by genes connected to arginine’s established molecular functions.
A more unexpected result involved three HLA genes responsible for producing MHC-1 (major histocompatibility complex class I) proteins. MHC-1 proteins appear on the surfaces of cells throughout the body. They display foreign or abnormal proteins to T cells, which then recruit other immune cells to respond to the threat.
MHC-1 contains many sites where arginine must be incorporated during production, so the researchers suspected that arginine scarcity was interfering with the process. Further experiments revealed exactly where production broke down.
When cells were deprived of arginine, ribosomes, the cellular machines that assemble proteins, stalled while trying to produce MHC-1. Without enough arginine, they could not complete the protein. As a result, cells displayed fewer signals capable of alerting T cells to cancer-related or viral proteins. This allowed potentially dangerous cells to escape immune detection more easily.
“These findings are exciting because they reveal that consumption of a specific amino acid can directly regulate gene expression in an organism by increasing production of a protein enriched in that amino acid,” Tavazoie says. “We believe that such selective translational tuning of gene expression through dietary manipulation likely extends to many other proteins and amino acids.”
Fewer Colon Tumors in Mice
Wu next tested how different amounts of dietary arginine affected mice. Animals fed a diet low in arginine developed more colon cancer tumors. Mice that received more arginine developed fewer colon tumors.
Working with Heinz-Heinrich Hoffman, a research assistant professor in Charles Rice’s Laboratory of Virology and Infectious Disease, Wu repeated the dietary studies using mouse models of influenza and SARS-CoV-2. The results followed a similar pattern and produced another surprising finding.
“Not only did mice with an arginine-rich diet have milder symptoms from viral infections, giving the mice arginine after influenza infection improved their outcomes too,” Wu notes. “That was very surprising. From our genetic models, we knew manipulating arginine levels had a strong effect on gene expression, but we didn’t expect the dietary manipulation to be equally impactful.”
Possible Implications for Aging and Disease
The findings suggest that falling arginine levels may help explain why poor nutrition and aging are associated with greater vulnerability to certain cancers and viral infections. Arginine levels naturally decrease with age, potentially weakening the immune system’s ability to recognize abnormal or infected cells.
“Qiushuang’s findings illuminate how poor diet and aging — during which arginine levels naturally decline — could create the perfect storm for the initiation of colon cancer. Similarly, age-related arginine loss could partially contribute to the greater mortality caused by respiratory viruses,” Tavazoie says. “We’re also investigating whether making dietary changes in other amino acids has beneficial effects in a variety of disease contexts. There are no doubt more discoveries to come.”