The protein quality control agent of bacteria provides insights into the origins of life

May 30 – The process of our cells to turn genes into useful proteins works the same way as the assembly line of a car factory. there are drawings, parts, workers, engines, quality control systems and even recycling teams. If the process of recycling the cell fails, abnormal protein fragments accumulate, potentially resulting in cell death. In nerve cells, the process is linked to various neurodegenerative diseases, including ALS and dementia.

A new study from Claudio Joazeiro's lab, Ph.D., published online in the journal Cell On May 30, we will discover how simpler organisms – bacteria and archaea – manage the recycling of incomplete proteins. The findings not only provide new directions for controlling the virulence of some of humanity's most dangerous pathogens, including listeria, staphylococcus and streptococcus, but they also affect our understanding of the evolution of life itself.

Joazeiro's group discovered that the mechanism was not so different from the one they had previously discovered in plant, animal and fungal cells.

"We know that cells make proteins, this process is sometimes interrupted because of errors," says Joazeiro, who works jointly at Scripps' Molecular Medicine Research Department in Jupiter, Florida, and at the Center for Biology. Molecular of the University of Heidelberg. in Germany.

"One of the problems with that is that the buildup of partially formed proteins can be toxic. So in our lab, we ask how do the cells perceive it, and how do they disassemble these proteins and recycle the basic components?

Organelles called ribosomes serve as engines for assembling proteins in cells. If they drop out during the process of reconstitution of the components (amino acids), the cells have various systems to react. In human cells and other eukaryotic cells, when a ribosome is blocked, rescue factors separate it. A protein called Rqc2, also known as NEMF, zooms in and recruits another protein – Ltn1 ubiquitin ligase, also called listerine. The Joazeiro laboratory had previously discovered that Ltn1 labeled the truncated protein fragment on ribosomes with a destruction label called ubiquitin. The protease saws then manage the demolition.

Highlighting the importance of this recycling process, Joazeiro discovered in 2009 that mutations of Ltn1 could cause the death of nerve cells in mice, leading to symptoms similar to ALS. Bacteria have related but somewhat more direct systems for treating the arrested ribosomes and their protein fragments, according to the Cell report. By studying B. subtilis bacteria, Joazeiro's team discovered that Rqc2 itself tagged the protein fragment with a flag, a polymer made up of the amino acid alanine. Thus reported, proteases cut off the bad fragment.

Previous studies have suggested that in some pathogenic bacteria, Rqc2 proteins have a different work, one that works outside the cell, helping to attach microbes to hosts.

"We have discovered that it is not all history," said Joazeiro. "Rqc2 plays a more fundamental role inside bacterial cells."

The next step will be to determine whether the defective virulence of Streptococcus strains lacking Rqc2 is primarily a consequence of their inability to recycle protein fragments within the cell. As more and more pathogens develop multiple resistance to antibiotics, understanding bacterial virulence may be particularly necessary.

For Joazeiro, it is equally important to understand that Rqc2 is a "living" molecular fossil, which sheds new light on the ancient ancestral organism that appeared 4 billion years ago to form the very basis of the tree of life that has evolved to become the biodiversity of the planet. .

"Shortly after cells invented protein manufacturing, they also had to figure out how to treat incompletely manufactured proteins," says Joazeiro. "The analyzes suggest that a Rqc2 peer of the last universal common ancestor has already performed this task."

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