Researchers from the UCSD School of Medicine and other universities across the country recently discovered that a protein previously thought to be of little importance plays a major role in regulating RNA levels and male fertility. The findings were published in the online journal Cell on March 31.
UPF3A was previously thought to be a weak activator of the Nonsense Mediated Decay pathway of mRNA, the molecule that communicates the genetic information used to create proteins. The NMD pathway works as a biological spell-check that reduces the expression of truncated, incorrectly constructed proteins and regulates normal gene expression.
UPF3A is one half of a gene paralog pair — duplicated from the same parent gene — that both play a role in governing the NMD pathway. UPF3A inhibits while UPF3B activates, and the opposite effects suggest they are the product of functional antagonism, a rare occurrence in gene duplication in which the proteins work in opposing ways to affect the same system. Miles Wilkinson, senior author and professor in the Department of Reproductive Medicine at UCSD School of Medicine, postulates that the relationship between the paralogs is analogous to a volume switch.
“Our results suggest that UPF3A and UPF3B act as volume controls to up and down-regulate NMD at the right times for normal development to proceed,” Wilkinson said.
He stated that they were able to determine UPF3A’s role by using a loss-of-function method.
“In papers from 10–15 years ago, UPF3A was found to largely lack much of any function, but in our publication we used a different test — a loss-of-function test — and found that actually, UPF3A is a potent inhibitor of the NMD pathway,” Wilkinson told the UCSD Guardian. “Loss-of-function means that a gene is mutated or in some other way debilitated so that it doesn’t work anymore. One then looks to see what goes wrong in the organism and what goes wrong must be what that gene normally does.”
The team then investigated the role of UPF3A on embryogenesis, the process through which an embryo forms and develops, by generating complete knockout UPF3A mouse models — engineered mice that do not produce the UPF3A protein. The models showed early embryonic death which, according to Jones, indicates that the NMD inhibitory function of UPF3A is also crucial in the very first stages of development in embryos.
Since UPF3A is highly expressed in the testes, the team also studied its impact on male fertility. The researchers knocked out UPF3A in sperm cells and found that it greatly reduces the number of cells in the testes that undergo meiosis, a process that produces more sperm and eggs.
Samantha Jones, co-first author and Ph.D. student in Wilkinson’s lab, said that NMD therapy could be beneficial due to its presence in various diseases.
“Since 15 to 30 percent of all human genetic diseases are caused by mutations detected by NMD, the range of genetic diseases potentially treatable by NMD therapy is vast,” Jones said in a press release.
Wilkinson elaborated on the medical implications of targeting NMD by suggesting scientists develop prescriptions that suppress UPF3A, which indirectly increases NMD activity resulting in fewer protein errors.
“To increase the effectiveness of the NMD pathway, drugs could be designed to inhibit UPF3A, as it is a natural suppressor of the pathway,” Wilkinson said in a press release. “Diseases that could potentially be treated include diabetes, amyotrophic lateral sclerosis and Marfan syndrome.”