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Apr. 25, 2008 Research Highlight Biology

Regulating antibody production

New insight into an important part of the immune response could lead to treatments for immune disorders

Image of test tubes

A RIKEN research group has puzzled out the molecular details of a key part of the complex communication network that regulates the production of antibodies by the immune system. The findings are an important step towards understanding immune disorders and how some types of tumors are initiated, as well as developing treatments for these conditions.

The work concentrates on the molecular events that occur immediately after an immune system B-cell is stimulated by a foreign body or antigen. From previous studies it is known that antigens bind with a surface protein known as a B-cell receptor (BCR) and that this triggers a complicated cascade of biochemical reactions involved in the immune response and its regulation.

One important biochemical pathway in this response involves two families of proteins called nuclear factor-κB (NFκB) and inhibitor of nuclear factor-κB kinase (IKK). Generally NFκBs are bound in the body of the cell to IKKs. When a BCR is triggered by an antigen, however, one consequence is the phosphorylation or addition of phosphate groups to IKKs which activates them to break up. This liberates NFκBs which can then enter the nucleus and interact with specific genes to trigger the immune response.

In a paper published recently in the Journal of Experimental Medicine 1, researchers from RIKEN’s Research Center for Allergy and Immunology in Yokohama led by Tomohiro Kurosaki describe work in which they were able to unravel the interactions of these molecules more precisely.

Two of the compounds known to be involved in the phosphorylation of specific amino acids in IKKs are protein kinase C β (PKCβ) and a complex called CBM built of three proteins: CARMA1, Bcl10 and MALT1. Using antibodies engineered to bind to and pinpoint amino acids which have phosphates added, the researchers found that PKCβ not only initiates the addition of phosphates to IKKs, but also adds phosphate directly to CARMA1 and this activates it to build the CBM complex. The researchers also found that one of the components of the IKK complex, IKKβ, phosphorylates CARMA1 as well. IKKβ therefore plays a positive feedback role when the IKK complex degenerates, amplifying the break down process.

“Both prolonged activation and inhibition of NFκBs are able at times to induce tumors,” says Hisaaki Shinohara, first author on the paper. “So the molecules included in this feedback loop provide good candidates as cancer drug targets.”

References

  • 1. Shinohara, H., Maeda, S., Watarai, H. & Kurosaki, T. IκB kinase β-induced phosphorylation of CARMA1 contributes to CARMA1-Bcl10-MALT1 complex formation in B cells. Journal of Experimental Medicine 204, 3285–3293 (2007). doi: 10.1084/jem.20070379

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