Research News

To understand how human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), causes cancer in infected patients, Cleveland Clinic researchers froze one of its most important molecules mid-motion.

The study, published in Nature Communications, used a technique called cryogenic electron microscopy (cryoEM), to flash freeze and take atomic-level pictures of a viral protein called ORF74. These images revealed ORF74’s structure, providing insight into how the protein drives cancer.

In healthy humans, proteins called G-protein coupled receptors (GPCR) send signals that tell cells to grow and divide. These signals are tightly regulated. They turn “on” when bound to specific molecules and stay “off” when unbound. KSHV rewrites these rules. It forces infected cells to produce a viral version of GPCR called ORF74 that’s always “on,” even when it’s empty. This relentless signaling drives uncontrolled cell division and tumor formation.

To understand why ORF74 is always on, researchers in the laboratory of Jae Jung, PhD used a cryoEM to zoom in on the frozen ORF74 and take atomic-level pictures of its structure. Dr. Jung is the director of the Sheikha Fatima bint Mubarak Global Center for Pathogen & Human Health Research. He and and his team work to develop therapies targeting virus-driven cancers, including KSHV.

“A protein’s job depends on its structure, just like how a car’s function depends on how its parts are organized,” explains study first author Junbae Park, PhD. “If we understand how a protein is built, we can figure out what it does and how to fix it when something goes wrong.”

The images showed a unique atomic arrangement found only in ORF74, unlike in typical GPCRs. The atomic positioning also makes the protein flexible enough to shift between shapes that keep it constantly "on," and signaling at high levels.

“Now we know how KSHV uses this protein to promote cancer, and it’s all in the protein’s shape,” Dr. Park says. “The next step is to think about how we can exploit its shape to stop it.”

For the next step of the KSHV project, Dr. Jung’s lab will team up with the laboratory of Feixiong Cheng, PhD, to test potential drug candidates that can block ORF74’s function.

Drs. Park and Jung hope to one day extend their research far beyond HHV-8 and Kaposi’s sarcoma.

“KSHV is not the only herpesvirus that has the ORF74 protein, but the signal strength of these proteins in other viruses vary widely," Dr. Park explains. “Our long-term goal is to understand the causes and effects of these different signaling activities in other viruses to develop more targeted, effective therapeutics.”