Damaged cells that no longer function properly voluntarily die to make way for new cells. The mechanism known as programmed cell death is “a normal physiological response and is critically important for normal mammalian development,” according to South Dakota State University assistant biology and microbiology professor Jaime Lopez. The National Human Genome Institute, for instance, likens the process to “leaves falling from a tree in the fall.”
However, genetic mutations can alter this important natural process. As a result, cell death goes unchecked leading to chronic, systemic inflammation in animals and humans.
Lopez is investigating an enzyme called linear ubiquitin assembly complex, or LUBAC, that plays a central role in regulating cell death. Understanding how fully functional LUBAC blocks the cell death pathway can help scientists learn how to treat patients with rare genetic mutations in LUBAC components that impair the enzyme pathway.
The basic cell biology research is supported by a five-year, nearly $1.3 million National Institutes of Health RO1 grant—this type of grant allows the recipient to apply for a competitive renewal award during the final year of the project. Lopez is recruiting two doctoral students to work on the project.
“I like to understand how cells function, how they stay alive, divide and grow and when they decide to die how those signals are executed,” said Lopez, who received his Ph.D. in biomedical sciences from the University of California, San Francisco. He came to SDSU in August 2017 after doing postdoctoral research at Goethe University’s medical school in Frankfurt for six years.
Discovery of genetic mutation in mice
The Jackson Laboratory, which breeds genetically engineered mice for scientific research, accidentally discovered a mouse within a colony that had a severe skin inflammation. “Mice (with this condition) end up scratching themselves and creating a wound,” Lopez said.
Analysis showed that the condition was linked to a genetic disorder that affects one LUBAC component. “That discovery places the LUBAC enzyme complex in the pathway that dictates inflammation and cell survival,” he said.
A few years later, a different mutation on the same gene was identified in a colony of mice in Holland, which also resulted in similar chronic systemic inflammation, Lopez continued. The researchers then looked for patients with similar symptoms that had not responded to treatment and identified mutations that affected the LUBAC components in humans.
These mutations are not associated with a particular disease, but present as a syndrome, Lopez said. The severity of the inflammatory condition depends on the degree to the enzyme’s function has been compromised. “Some mutations are lethal—the offspring do not survive.”
Learning how LUBUC works
LUBAC promotes the activation of prosurvival genes and actively suppresses spontaneous cell death, Lopez said. “Three proteins must come together to produce a signal that tells the cell to die. LUBAC somehow prevents them from coming together.” However, he continued, "We don’t understand how it does this—that is what the grant is about.”
What scientists do know is that LUBAC decorates target proteins with another protein called ubiquitin thereby connecting them into a long chain. Lopez suspects the genetic mutations in LUBAC components changes the way the ubiquitin chains are assembled thereby modifying their signaling and sending them to be degraded.
Lopez first hopes to determine how LUBAC is able to decorate proteins and then which are the most important protein targets that must be decorated to block spontaneous and inflammatory forms of cell death.