Slow proteins may contribute to many chronic diseases

Sometimes, life can be a real drag—especially if you’re a protein weighed down by unwanted baggage. Researchers have unveiled evidence that these ponderous proteins could be involved in a range of chronic diseases, including type 2 diabetes and inflammatory disorders—a finding that might eventually lead to entirely new treatment strategies (Cell 2024, DOI: 10.1016/j.cell.2024.10.051).

Some proteins can move fast enough to traverse a cell in mere seconds, even though they have to battle their way through bustling crowds of biomolecules to reach their targets.

But in 2022, a team led by Richard A. Young of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology studied liver cells from people with type 2 diabetes and found that their insulin receptor proteins were less mobile and consequently less effective at sensing insulin. This protein mobility problem was apparently worsened by reactive oxygen species (ROS) in the cells (Nat. Commun. 2022, DOI: 10.1038/s41467-022-35176-7). “The proteins just slowed down,” says Young.

ROS such as hydrogen peroxide are constantly being produced as part of normal metabolism. Some ROS play key roles in processes such as cell signaling, but they can also damage DNA and other cell components, so various cellular mechanisms keep them in check. But in many chronic conditions, including diabetes, those protections don’t work so well, leading to higher ROS levels.

Young’s team recently used fluorescence microscopy to confirm that ROS can cause mobility problems in a range of other proteins bearing cysteine amino acid residues on their surfaces. The researchers used hydrogen peroxide to simulate elevated ROS levels in cells, which caused surface cysteines to form disulfide bonds with other proteins, creating bulky protein dimers or larger aggregates with 20–35% lower mobility. Since slow proteins collide less often with their targets, this reduces their overall function in the cell, an effect the researchers call “proteolethargy.”

Roughly half of known human proteins contain at least one surface cysteine, making them potentially susceptible to proteolethargy, and the researchers believe that this mechanism could be at play in many chronic diseases. The team also found that the antioxidant N-acetyl cysteine could partially restore protein mobility in the cells by reducing ROS, which might pave the way for fruitful drug design approaches for chronic conditions.

“I think it’s potentially interesting,” says Helena M. Cochemé, who studies redox biology at the MRC Laboratory of Medical Sciences and was not involved in the research. But she points out that the researchers used much higher concentrations of hydrogen peroxide than would normally be expected in cells. “It’ll be really important to see how this actually translates to in vivo,” she says.

Young is so confident in the proteolethargy concept that he has refocused most of his team’s research to investigate it further, and he says the hypothesis seems to be holding up so far. “I’m delightfully surprised that every time we ask a new question, this model is accurate in its predictions,” he says.