A new study by researchers at the VIB-UGent Center for Medical Biotechnology and collaborators demonstrates how a protein linked to the human immune system lures and traps HIV-1 and herpes simplex virus-1. The findings revealed the protein MX2 assembles structures in the cell that lure in these viruses and then trap them or even take them apart.

The research was published in Cell Host and Microbe in an article titled, “MX2 forms nucleoporin-comprising cytoplasmic biomolecular condensates that lure viral capsids,” and led by researchers at VIB-UGent in collaboration with researchers at Hannover Medical School, KU Leuven, and Ghent University.

“Human myxovirus resistance 2 (MX2) can restrict HIV-1 and herpesviruses at a post-entry step through a process requiring an interaction between MX2 and the viral capsids,” the researchers wrote. “The involvement of other host cell factors, however, remains poorly understood. Here, we mapped the proximity interactome of MX2, revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacted with these proteins to form multiprotein cytoplasmic biomolecular condensates that were essential for its anti-HIV-1 and anti-herpes simplex virus 1 (HSV-1) activity.”

The innate immune system of the human body can sense and respond to viruses by producing alarm cytokines, most notably interferons. These proteins act as an alarm system that goes off when a cell is infected by a virus. These defenses comprise so-called interferon-stimulated genes (ISGs), which produce specific proteins with antiviral qualities. One example of this is the MX protein, which was discovered 60 years ago and was found to restrict a broad range of viruses, including those that cause AIDS and herpes.

The researchers were unsure how the antiviral properties of the MX protein worked. However, after mapping the proximity interactome of MX2 and observing how MX2 interacts with other cells, the researchers uncovered the secret of the MX protein’s antiviral activity.

A herpes or HIV virus delivers its genome in the host cell nucleus through the nuclear pore complex. This delivery is essential for the virus to launch its genetic program, hijack the cell’s machinery, and propagate. As a result, new viruses are made, that leave the cell and spread to surrounding cells.

The researchers observed how the MX protein drives the assembly of virus decoy structures that mimic nuclear pore complexes.

“We noticed that incoming viruses were being lured into structures that resembled nuclear pores,” explained Sven Eyckerman, PhD, a scientist at the VIB-UGent Center for Medical Biotechnology. “Through proteomics screens, we found that the MX protein interacts with proteins that are part of the nuclear pore complex. On closer inspection, we discovered that the MX protein orchestrates the assembly of nucleoporins into biomolecular condensates, membrane-less droplets inside a cell that act like a separate compartment. Viruses mistake these condensates for the actual cell door to the cell nucleus and get trapped or punctured.”

“By tricking viruses into prematurely releasing their genetic material, the MX protein ultimately prevents the spread of viral infections,” added Xavier Saelens, PhD, professor and group leader at the VIB-UGent Center for Medical Biotechnology. “This discovery not only clarifies how MX proteins combat viruses but also opens up potential new avenues for antiviral therapies.”

The new findings could be used to devise new strategies to combat these viruses.

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