Chronic diseases such as type 2 diabetes and inflammatory diseases have a huge impact on humanity. They are a major cause of disease burden and death around the world, are physically and economically burdensome, and the number of people with such diseases is increasing.
Treating chronic diseases has proven difficult because there is no single simple cause, such as a single gene mutation, that could be targeted for treatment. At least that is the view of scientists. However, a study by Whitehead Institute member Richard Young and colleagues, published in the journal Cell, shows that many chronic diseases have a common denominator that could cause their dysfunction: reduced protein mobility. This means that about half of all proteins active in cells slow down their movement when cells are in a chronic disease state, limiting the proteins’ functions.
The researchers’ findings suggest that protein mobility may be a critical factor in reduced cell function in chronic disease, making it a promising therapeutic target. In this article, Young and colleagues in his lab, including postdoctoral researcher Alessandra Dall’Agnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ihn Lee, describe their discovery of this common mobility defect, which they call proteolethargy. They explain what causes the defect and how it leads to dysfunction in cells, and propose a new therapeutic hypothesis for the treatment of chronic diseases.
When Proteins Do Not Complete Their Tasks on Time, Various Problems Occur in the Cells
How can proteins that move more slowly through a cell lead to widespread and significant cellular dysfunction? Dall’Agnese explains that each cell is like a small city, with proteins as the workers that keep everything running. Proteins have to shuttle in dense traffic in the cell and get from their place of origin to their place of work. The faster they travel, the more work they can do. The slowing down of processes in cells with limited protein mobility follows a similar course.
Normally, most proteins move back and forth in the cell, bumping into other molecules until they find the molecule they are working with or acting on. The slower a protein moves, the fewer other molecules it reaches and the less likely it is to be able to do its job. Young and his colleagues found that slowing down proteins in this way leads to a measurable reduction in the proteins’ functional performance. If many proteins do not complete their tasks on time, various problems occur in the cells – as is known in chronic diseases.
Discovery of the Problem of Protein Mobility
Young and his colleagues initially suspected that there might be a problem with protein mobility in cells affected by chronic disease after observing changes in the behavior of the insulin receptor, a signaling protein that responds to the presence of insulin and causes cells to take up sugar from the blood. In people with diabetes, cells respond less to insulin – a condition known as insulin resistance – leaving too much sugar in the blood. In a study on insulin receptors published in Nature Communications in 2022, Young and colleagues reported that the mobility of the insulin receptor could be relevant to diabetes.
Since it is known that many cellular functions are altered in diabetes, the researchers considered the possibility that altered protein mobility could affect many proteins in cells. To test this hypothesis, they examined proteins involved in a variety of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in ribosome production; and SRSF2, a protein involved in messenger RNA splicing. They used single-molecule tracking and other methods to measure how each of these proteins moved in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the diseased cells.
Many Processes Rely on the Efficient Functioning of Proteins
Next, the researchers had to find out what caused the proteins to slow down. They hypothesized that the defect was related to an increase in the level of reactive oxygen species (ROS) in the cells, molecules that are very prone to interfere with other molecules and their chemical reactions. Many types of chronic disease triggers, such as higher sugar or fat levels, certain toxins and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers re-measured protein mobility in cells that had high levels of ROS and were otherwise not in a disease state and found comparable mobility defects, suggesting that oxidative stress was responsible for the protein mobility defect.
The final piece of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only protein that was not affected in the experiments, and it had a distinct difference from the others: its surface did not contain cysteines, an amino acid building block of many proteins. Cysteines are particularly susceptible to disruption by ROS, as they cause them to bind to other cysteines. When this binding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as each protein can on its own.
About half of the proteins in our cells contain surface cysteines, so this single protein mobility defect can affect many different cellular signaling pathways. This makes sense when you consider the variety of dysfunctions that occur in cells of people with chronic diseases: Dysfunction in cell signaling, metabolic processes, gene expression and gene silencing, and more. All of these processes rely on the efficient functioning of proteins – including the various proteins studied by the researchers. Young and his colleagues conducted several experiments to confirm that reduced protein mobility does indeed impair a protein’s function. For example, they found that an insulin receptor whose mobility is reduced acts less efficiently on IRS1, a molecule to which it normally adds a phosphate group.
Development of Drugs that Work Across the Entire Spectrum of Chronic Diseases
The discovery that reduced protein mobility in the presence of oxidative stress could cause many of the symptoms of chronic disease offers opportunities to develop therapies to rescue protein mobility. As part of their experiments, the researchers treated cells with an antioxidant called N-acetylcysteine, which reduces ROS, and found that this partially restored protein mobility.
The researchers are pursuing a number of follow-up projects to this work, including the search for drugs that safely and efficiently reduce ROS and restore protein mobility. They have developed a test that can be used to screen drugs for their ability to restore protein mobility by comparing the effect of each drug on a simple biomarker with and without surface cysteines. They are also investigating other diseases that may be related to protein mobility and exploring the role of reduced protein mobility in ageing.
“The complex biology of chronic diseases has made it difficult to generate effective therapeutic hypotheses,” says Young, who is also a professor of biology at the Massachusetts Institute of Technology. “The discovery that different disease-associated stimuli all induce a common feature, proteolethargy, and that this feature may contribute to much of the dysregulation seen in chronic disease is something that researchers hope will fundamentally change the development of drugs that work across the spectrum of chronic disease.