When a crucial enzyme is dotted with targets that summon an attack by a cell's protein-destroying complex, another molecule comes to the rescue, blinding the attacker by wiping off the targets.
The enzyme, called TRAF3, survives to control a molecular network that's implicated in a variety of immune system-related diseases if left to its own devices.
University of Texas MD Anderson Cancer Center scientists identified TRAF3's savior and demonstrated how it works in a paper published online this week in Nature.
By discovering the role of OTUD7B as TRAF3's protector, Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology, and colleagues filled an important gap in their understanding of a molecular pathway discovered in Sun's lab.
"Genetic defects or constant degradation of TRAF3 lead to the uncontrolled activity of what we call the non-canonical NF-kB pathway. This in turn, is associated with autoimmune diseases and lymphoid malignancies such as multiple myeloma and B cell lymphomas," Sun said. "Understanding how the degradation of TRAF3 is regulated is extremely important."
Dodging annihilation, turning the tables
Sun earlier found an alternative, or non-canonical, pathway that activates the protein complex known as NF-kB, a family of proteins that turns on genes that are important in immune response, inflammation, cell growth and survival, and development.
They found that NF-kB activity increases when TRAF3 is tagged with the homing targets, called ubiquitins, and is destroyed by the proteasome, a complex of proteins that hunts down ubiquitin-decorated proteins.
When TRAF3 evades attack, it turns that same destructive mechanism against a protein that's central to NF-kB activity, tagging it with ubiquitins. .
The key question was: What regulates TRAF3's destruction and, in the process, controls NF-kB?
Sun and colleagues had a candidate, the enzyme OTUD7B, also known by its more lyrical name, Cezanne. It was genetically quite similar to another enzyme active in the canonical pathway for NF-kB called A20. Both are deubiquitinases, enzymes that cleave ubiquitin polymers.
By applying inducers of the non-canonical NK-kB pathway to cells derived from OTUD7B-deficient mice, the researchers found:
- Degradation of TRAF3 and resultant accumulation of its target protein
- Ubiquitination of TRAF3
- Cells with OTUD7B intact suppressed non-canonical NF-kB signaling.
Mice with OTUD7B suppressed had greatly increased lymphoid cell growth in the lining of the intestine and hyper-responsiveness to antigens by B cells. "If these two symptoms occur persistently, as they did in the knockout mice, they may contribute to autoimmunity or inflammation," Sun said.
However, knockout mice also had an improved immune response to the lethal intestinal bacterial pathogen C. rodentium. All of the mice with normal OTUD7B died of the bacterial infection, while 75 percent of the knockout mice survived.
Understanding these effects and developing OTUD7B as a target for inhibitors to boost immunity in the lining of the intestine will take more research, Sun says.
MD Anderson news release