New understanding of male fertility from enzyme discovery

Aug 3 2007

Scientists have discovered a new enzyme involved in the degradation of proteins inside cells, a process that helps eliminate or recycle proteins that are no longer needed.

The unexpected discovery, made by Marcus Groettrup, chair of the immunology department at the University of Constance, Konstanz, Germany, and colleagues, overthrows the idea that protein degradation is initiated by only one enzyme. Also, the new enzyme is very highly expressed in the testis, which could provide a new understanding of male fertility.

"We essentially found that cleanup in the cell is not supervised by one but by two proteins," Groettrup says. "It is important because everything we know about this cleanup process assumes that only one enzyme initiates it. The second protein we discovered may either share some functions with the first one or do totally different things."

The new study, to be published in the August 3 issue of the Journal of Biological Chemistry, was selected as a 'Paper of the Week' by the journal's editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.

Before being degraded, proteins are ,tagged, with a small protein called ubiquitin. Three types of enzymes are involved in the tagging process. An enzyme called activating enzyme E1 first activates ubiquitin and binds to it. Then the ubiquitin is transferred to a second enzyme called ubiquitin-conjugating enzyme E2. And a third enzyme, called ubiquitin ligase E3 binds to both E2 and the protein to be degraded, so that E2 can transfer the ubiquitin to the protein. By binding to other ubiquitin-carrying E2 enzymes, E3 transfers many ubiquitins to the protein, signaling to the cell that the protein needs to be degraded.

Until now, only one type of E1 enzyme for ubiquitin has been known to exist in the human genome, while 34 E2 enzymes and 531 E3 enzymes have been discovered. Because of the large number of E2 or E3 enzymes that have been found, researchers are more likely to find another E2 or E3 enzyme than a new E1 enzyme, which explains why Goetrrup and his colleagues were very surprised to stumble upon one.

"You can picture E1 as the Federal Reserve Bank," Goettrup says. "Until now, scientists have shown that, in all the protein degradation processes that use ubiquitin, E1 is the master bank that distributes money (ubiquitin) to other banks (the E2 enzymes), which then give out credits to their clients (the E3 enzymes). What we found is another Federal Reserve Bank, bringing questions like: "What are the clients of this new master bank?' and, 'Are there other master banks that we haven't found yet?' It makes us rethink protein degradation in completely new ways."

The scientists were searching for an enzyme similar to E1 that activates a protein that looks like ubiquitin called FAT10. Surprisingly, the enzyme they found could not activate FAT10 but instead activated ubiquitin itself. The researchers then tested whether this enzyme, which they called UBE1L2, also helped degrade proteins by working with E2 and E3 enzymes. They confirmed that this was indeed the case.

Groettrup and his team also tested whether UBE1L2 was - like the original E1 - expressed in all organs and tissues. They measured the expression levels of UBE1L2 in mice and found that the protein was expressed about five times more in the testis than other organs.

"Again, this was totally unexpected," Goettrup says. "Unlike the first E1, UBE1L2 might have a specialized role in tissues and in particular in the testis. Going back to the previous analogy of the Federal Reserve Bank, this result shows that UBE1L2's ,main client banks, may be in the testis and that UBE1L2 controls many of the protein degradation processes in that organ."

Goettrup and colleagues are now planning to investigate which E2 and E3 enzymes work with UBE1L2 and determine whether they also work with the original E1. The scientists also would like to investigate a potential role for UBE1L2 in male fertility and determine why the enzyme is more highly expressed in testes than in ovaries.