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 were known deubiquitinases, enzymes that cleave ubiquitin polymers. A20 is not active in the non-canonical NFkB pathway.
By applying inducers of the non-canonical NK-kB pathway to cells derived from OTUD7B-deficient mice, the researchers found:
Cells with OTUD7B intact suppressed non-canonical NF-kB signaling.
Varied immune effects in mice
Knocking out the OTUD7B gene caused biological changes in mice, but it did not kill them, as occurs when A20 is knocked out.
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.
Teasing out the reasons for these effects and developing OTUD7B as a target for inhibitors to boost immunity in the lining of the intestine will take more research, Sun said.
"It's important to know that TRAF3 has opposing roles in regulating activation of T cells and B cells, indicating that OTUD7B has a cell-type specific function. So, as with many other research findings, it might take considerably more effort to assess the therapeutic potential of OTUD7B," Sun said.
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center