Scientists sheds light on small protein and its role in immune response

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The immune system is the body’s defense against disease-causing pathogens. It works by warding off disease and potentially-damaging foreign bodies. Now, a team of researchers have developed a new method to shed light on the basic defense mechanism of the immune system.

Researchers at the University of Iowa (USA) and VIB-UGent Center for Medical at Ghent University identified ISG15, an interferon-stimulated, ubiquitin-like protein, that contains anti-viral and anti-bacterial properties.

Structure of the ISG15 protein. Credit: Emw - Own work, CC BY-SA 3.0,
Structure of the ISG15 protein. Credit: Emw - Own work, CC BY-SA 3.0,

The new method, which was described in the study published in the journal Nature Communications, can help scientists to determine and study proteins tagged with ISG15. The method can unveil the many functions of ISG15 in fighting infection and disease, eventually leading to the formulation of new antimicrobial drugs.

ISG15 tags proteins

Proteins are important molecules in the body, specifically expressed by cells during biological processes. A chemical tag works by attaching to a protein to modify and regulate its activity. This way, the body has control over the expressed proteins.
Ubiquitin is a small regulatory protein that is found in almost all cellular tissues. It helps regulate the processes of other proteins in the body.

Now, the scientists discovered an ubiquitin-like modification dubbed as ISG15, which attaches itself to target proteins. Though ubiquitin and ISG15 share the same amino acid sequences at their end, the molecular function of ISG15 is still unclear, since the exact sites of modification and the modified proteins are still unknown.

To land to their findings, the scientists developed a new technology to determine modification sites of ubiquitin and use them to track and detect ISG15 modification sites.

Tracking ISG15

Though these two share common characteristics, as stated previously, ISG15 is not present under normal conditions and it’s only expressed upon certain stresses, including an infection caused by viruses or bacteria. The researchers need to test their approach or new method with an infection model.

The researchers tested the new approach after infecting mice with Listeria monocytogenes, a gram-positive bacterium that causes listeriosis. They then mapped the endogenous in vivo ISGylome in the liver after the infection by combining murine models of decreased or increased ISGylation with quantitative proteomics.

"As infection model we chose the bug Listeria monocytogenes. Leading to the 'old French cheese disease', Listeria is a food-borne bacterial pathogen hiding from the immune system inside host cells." Fabien Thery of the Impens lab and co-first author of the study, said.

The researchers chose the liver since it’s a central player in metabolism and at the same time, works as a blood filter to detect and eradicate any potential threats in the body, including pathogens.

They identified about 930 ISG15 sites in 434 proteins, and at the same time, detected changes in the host ubiquitylome. They also found that ISG15 targets many enzymes that play major roles in metabolic processes. They also act on key regulators of autophagy, the body’s way of cleaning out damaged cells to regenerate healthier ones. This process can help in antibacterial actions and the study hints that ISG15 controls this process.

The researchers concluded that there is a connection among ISG15, autophagy and cellular metabolism. Now, the researchers are working on to investigate specific targets of the protein tag during infection with other disease-causing microorganisms such as the Coxsackie virus and the influenza virus.

The new study findings can help unravel new methods that can help develop drugs. Infections are becoming more common today and new diseases emerge, hence, making it harder for doctors to treat their patients. Finding more ways on how to boost the immune system or studying how it works can help develop new drugs to fight these pathogens.

Journal reference:

Zhang, Y., Thery, F., Wu, N.C. et al. The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection. Nat Commun 10, 5383 (2019) doi:10.1038/s41467-019-13393-x,

Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.


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