Scientists find protein that reins in runaway network

January 22, 2013

Marked for death with molecular tags that act like a homing signal for a cell's protein-destroying machinery, a pivotal enzyme is rescued by another molecule that sweeps the telltale targets off in the nick of time.

The enzyme, called TRAF3, lives on to control a molecular network that's implicated in a variety of immune system-related diseases if left to its own devices.

The University of Texas MD Anderson scientists identified TRAF3's savior and demonstrated how it works in a paper published online Sunday in Nature.

By discovering the role of OTUD7B as TRAF3's protector, Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of , and colleagues filled an important gap in their understanding of a molecular pathway discovered in Sun's lab.

" 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 and such as and 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 has the homing targets, called ubiquitins, attached to it and is destroyed by the , a complex of proteins that hunts down ubiquitin-decorated proteins.

When TRAF3 evades attack, it turns that same destructive mechanism against NIK, a protein that's central to NF-kB activity, by tagging it with ubiquitins.

The key question was: What regulates TRAF3's destruction and, in the process, controls NF-kB?

OTUD7B emerges

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:

  • Degradation of TRAF3 and accumulation of its target, NIK
  • Ubiquitination of TRAF3
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 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.

Explore further: Researchers find new drug target for lung cancer

Related Stories

Researchers find new drug target for lung cancer

February 16, 2012
Drugs targeting an enzyme involved in inflammation might offer a new avenue for treating certain lung cancers, according to a new study by scientists at the Salk Institute for Biological Studies.

Researchers discover molecular link between circadian clock disturbances and inflammatory diseases

August 1, 2012
Scientists have known for some time that throwing off the body's circadian rhythm can negatively affect body chemistry. In fact, workers whose sleep-wake cycles are disrupted by night shifts are more susceptible to chronic ...

A boost in microRNA may protect against sepsis and other inflammatory diseases

May 24, 2012
Acute inflammatory diseases, such as sepsis, as well as chronic inflammatory diseases like diabetes and arthritis, develop as a result of sustained inflammation of the blood vessel wall. Researchers at Brigham and Women's ...

Recommended for you

Make way for hemoglobin

August 18, 2017
Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is ...

Bio-inspired materials give boost to regenerative medicine

August 18, 2017
What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

New technique overcomes genetic cause of infertility

August 17, 2017
Scientists have created healthy offspring from genetically infertile male mice, offering a potential new approach to tackling a common genetic cause of human infertility.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.