The anti-infection protein also detects the erroneous folding of proteins in uninfected cells

Researchers at the University of Toronto have discovered an immune mechanism by which host cells fight bacterial infection and have also discovered that an essential protein in this process can detect misfolded proteins in all mammalian cells and respond to them.

The protein is called a regulated heme inhibitor or HRI, and the researchers have shown that during a bacterial infection, it triggers and coordinates a chain reaction among other proteins forming a larger complex . This larger group or "signalosome" boosts inflammation and leads to an anti-bacterial response.

But HRIs can also regulate protein folding in other types of cells, researchers have shown. The protein folding, which helps to determine the 3D form of a protein and is essential to its function, is involved in non-infectious diseases, including neurodegenerative disorders of Parkinson's, Alzheimer's and ALS.

"The innate immune function we have discovered is essentially a protein scaffolding mechanism, which is important because you want a quick and orderly response to bacterial infections," said Stephen Girardin, professor of medicine and pathobiology of laboratory and immunology at the University of Toronto. "But we also found that the same pathway is important for scaffolding and aggregation of proteins in other cells, which opens up promising research prospects for neurodegenerative and other diseases."

The newspaper Science published the results today.

Researchers have studied HRI for more than three decades, but mainly in the context of red blood cell disorders. "This protein appears in all mammalian body cells and has been recognized as a wide or near-promiscuous sensor," said Mena Abdel-Nour, lead author of the journal, who completed her PhD in Girardin's laboratory at beginning of this year. "But he was neglected in relation to pattern recognition molecules and the formation of amyloid-type structures, so we had to test his role in different ways before believing what we saw."

Abdel-Nour and his colleagues have developed a new technique for studying the effects of HRI. They adapted a biochemistry analysis from the laboratory of Jeffrey Lee, a professor of laboratory medicine and pathobiology at the University of Toronto, whose team works alongside theirs, which allowed them to distinguish folded proteins from misfolded proteins when looking at protein aggregates. Scientists have struggled to make this distinction in part because most of the available tests only work in specimens and are not adaptable to cells.

Researchers have early preclinical data showing that HRI could protect against the type of neurodegeneration observed in Parkinson's disease. "Speculatively, it may be possible to find molecules that produce the protective effects of HRI, which could lead to real therapy," said Abdel-Nour, who plans to pursue a career as a biotech and healthcare consultant. health. Current treatments for Parkinson's disease are focused on finding and eliminating protein aggregates, rather than repairing cell defects before these clusters accumulate.

Girardin says he's determined to continue this research in collaboration with neuroscientists, and he just received funding to support this work. "We are focusing on Parkinson's disease because it is a very important disease for human health and because it is characterized by the aggregation of proteins in the cells." So perhaps is an ideal model for testing this new way. "

Next steps include biochemical studies of IRH and associated complexes during protein folding, as well as animal studies on neurodegenerative diseases to further validate the new pathway, which shares many features with a similar pathway in the human being. human.