Infection-fighting protein senses protein misfolding in non-infected cells, U of T researchers find

Researchers at the University of Toronto have uncovered an immune mechanism where host cells combat bacterial infection – and that a protein crucial to the process can sense and respond to misfolded proteins in all mammalian cells.

The protein is called heme-regulated inhibitor, or HRI, and the researchers showed that during bacterial infection it triggers and co-ordinates a chain reaction among other proteins that form a larger complex. That larger group, or signalosome, amplifies inflammation and leads to an anti-bacterial response.

But HRI can also regulate protein folding in other cell types, the researchers showed. Protein folding, which helps determine the 3D shape of a protein and is essential for its function, plays a key role in non-infectious diseases such as the neurodegenerative disorders Parkinson’s, Alzheimer’s and Amyotrophic Lateral Sclerosis, or ALS.

The findings were published recently in the journal Science.

“The innate immune function that we discovered is essentially a mechanism of protein scaffolding, which is important because you want a quick and orderly response to bacterial infection,” says Stephen Girardin, a professor in U of T’s department of laboratory medicine and pathobiology and the department of immunology in the Faculty of Medicine.

“But we also found that same pathway is important for protein scaffolding and aggregation in other cells, which opens promising research angles for neurodegenerative and other diseases.”

Researchers have studied HRI for over three decades, but mostly in the context of red blood cell disorders. “This protein appears in all cells in the mammalian body and was recognized as a broad or promiscuous sensor,” says Mena Abdel-Nour, the paper’s lead author. “But it was overlooked relative to pattern recognition molecules and the formation of amyloid-like structures. We had to test its role in several different pathways before we believed what we saw.”

Abdel-Nour, who completed his doctorate in Girardin’s lab earlier this year, and his colleagues developed a novel technique to study the effects of HRI. They adapted a biochemistry assay from the lab of Jeffrey Lee – an associate professor of laboratory medicine and pathobiology – which helped them distinguish between folded and misfolded proteins when looking at protein aggregates. Scientists have struggled to make that distinction in part because most available tests only work in test tubes and are not adaptable to cells.

The researchers have early pre-clinical data that shows HRI could protect against the type of neurodegeneration seen in Parkinson’s. “Speculatively, it might be possible to find molecules that produce HRI’s protective effects, which could lead to a bona fide therapy,” says Abdel-Nour, who plans to pursue a career as a biotechnology and health-care consultant. Current therapies for Parkinson’s focus on finding and clearing out protein aggregates, rather than fixing cellular defects before those clusters accumulate.

Girardin says he is committed to pursuing the research in collaboration with neuroscientists, and that he just received funding to support the work. “We are focused on Parkinson’s because it’s a very important disease for human health, and because its hallmark is protein aggregation inside cells, so it may be a perfect model to test this new pathway.”

Next steps include biochemical investigations of HRI and related complexes during protein misfolding, and animal studies of neurodegenerative disease to further validate the new pathway, which shares many features with a similar pathway in humans.

Several researchers collaborated on the study including Dana Philpott, a professor of immunology at U of T, and Damien Arnoult, a professor at INSERM, France’s national institute of health and medical research.

The research received support from the Canadian Institutes of Health Research.