May 24, 2017 4:00 AM

Revealed: How a Virus Tricks Cells into Helping It Build an Invasion Route

Polyomavirus harnesses cellular “motors” to bring together the supplies that can build a portal for itself, researchers show.

Our cells run like individual tiny factories that make specialized products, using the carefully guarded instructions kept in the CEO’s office.

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Every once in a while, an invader tries to get inside and hijack the whole works, through a combination of industrial espionage and hostile takeover. If the invader succeeds in getting into the CEO’s office — the nucleus, where the DNA plans are kept — things don’t end well for the original factory.

Scientists still don’t know how viruses accomplish this invasion without getting caught by the factory security guards. But new research from the University of Michigan reveals important clues about one of the most mysterious types, called polyomaviruses.

The findings could aid the search for new treatments or preventive strategies against the problems that polyomaviruses can cause, including the deadly skin cancer Merkel cell carcinoma, and the fatal problems in people who are immunocompromised because of organ transplants and cancer treatment.

"From the cell’s point of view, it’s a mild process. Only a few virus particles end up being successful — but once they are, they can reach the nucleus, letting a wild gang of thieves loose."
Madhu Sudhan Ravindran, Ph.D.

Hijacking the forklifts

Publishing in Nature Communications, the team reports that polyomavirus fools the cell into building the very doorway that can let the virus get close to the nucleus. A few more steps, and the virus can take over the whole factory.

“Our results suggest polyomavirus hijacks a kind of cellular molecular motor whose normal job is to transport cargoes, and uses it to build a penetration site or portal,” says Billy Tsai, Ph.D., the Corydon Ford Collegiate Professor in the Department of Cell and Developmental Biology. Tsai worked with postdoctoral fellow Madhu Sudhan Ravindran, Ph.D., and others to make the discovery.

That kind of motor — called kinesin-1 — acts like an army of forklifts in the factory. Each kinesin-1 molecule travels along tiny stiff paths called microtubules, carrying loads of proteins where they need to go inside the cell in order to build the cell’s products.

According to the new findings, each polyomavirus particle tricks some of these forklifts into bringing just what the virus needs to build its own door. Once built, that door leads into the waiting room outside the CEO’s office — the area inside the cell nearest the nucleus.

“From the cell’s point of view, it’s a mild process,” says Ravindran. “Only a few virus particles end up being successful — but once they are, they can reach the nucleus, letting a wild gang of thieves loose.”

This is the first time scientists have identified the mechanism behind this key step of the invasion.

It’s possible the new findings may one day lead to tools to fight Merkel cell cancer or other polyomavirus diseases that affect organ transplant recipients, HIV/AIDS patients and cancer survivors.

For now, it’s too early to say for certain, says Tsai. But he notes some drug companies are already working on medications that block other cellular motors and keep cancer cells from dividing.

This video shows live-cell imaging of protein 'focus' points created in the endoplasmic reticulum membrane after polyomavirus infection. Time sequences of the images are shown at the top left corner and indicate time after addition of linker drug. The different color arrows (yellow, blue and pink) represent small foci that fuse into a larger focus (yellow and blue to green and then green and pink to red) over time.

More about the study

Tsai and Ravindran also worked with Kristen Verhey, Ph.D., the interim chair of cell and developmental biology at U-M, and her postdoctoral fellow Martin Engelke, Ph.D. They developed the specialized tools that allowed researchers to see activity along the microtubules and other structural skeleton elements inside cells.

SEE ALSO: Can Math Help Explain Our Bodies — and Our Diseases?

The team used a polyomavirus that infects monkeys but not people — called SV40 — and looked at how it interacted with the membrane that encloses the endoplasmic reticulum, or ER.

Inside each cell factory, the ER is the factory floor. It’s where the orders from management are processed and where products made from raw materials are packaged up to ship out.

Scientists already knew that polyomaviruses enter our cells by picking a lock in the factory wall — and riding in a cellular compartment called an endosome straight into the ER.

But once in the ER, the viruses had seemed trapped, unlike some types of viruses that have clear escape mechanisms.

The new research shows how polyomaviruses mount this escape: tricking the kinesin-1 forklifts to bring the supplies the virus needs.

If enough virus particles get this to happen in several areas of the ER membrane, they can move toward one another along the microtubule paths and create a site where the ER membrane can be penetrated — which U-M researchers call a “focus.”

While many kinesin molecules travel along straight microtubules stretching from the ER to the outer edges of cells, the researchers show that kinesin-1 especially likes to travel along specially tagged microtubules that curve to remain near the nucleus. That makes it ideal for constructing that “focus” point and allowing the virus to escape the ER into the space near the nucleus.

Polyomaviruses aren’t the only viruses that lack an envelope, or membrane, that could make it easier for them to bind with our cells’ own outer and ER membranes.

Poliovirus and papillomavirus, which can cause cervical cancer, among other diseases, are among other non-enveloped viruses that also have to figure out a way to breach both cell and ER membranes. The viruses are too big to use existing openings. So the new research may aid understanding of them, too.

The exact way a polyomavirus summons those forklifts still isn’t clear, but Tsai and Ravindran are working on finding it.

They’re also studying how a polyomavirus later manages to infiltrate the CEO’s office — the nucleus — and inject its own genetic material. This allows the virus to hijack the factory to copy itself, then self-destruct to send new viruses into the body.

“Only a few particles end up being successful, with only 1 to 2 percent reaching their final destination,” Tsai says. “They have to be able to do that without destroying the normal function of kinesin-1. Now that we understand this, our goal should be finding a way to destroy this specific kind of motor activity without harming the infected cell.”