The protein TRAF6 is essential for the operation of many physiological processes, ranging from the development of sweat glands and the formation of bone to the operation of the innate immune system. TRAF6 is an E3 ubiquitin ligase and, for many years, it has been widely accepted that it is this enzymatic activity that mediates the essential functions of the protein. However, in a paper that the Cohen lab have just published in Proceedings of the National Academy of Sciences (http://www.pnas.org/content/114/17/E3481.short) they generated a mouse in which TRAF6 was replaced by a slightly modified protein devoid of E3 ligase activity. Remarkably, they found that the mice had normal sweat glands and bones and that much of the innate immune signaling network controlled by TRAF6 was intact. They went on to show that the E3 ligase activity of TRAF6 was not essential for innate immunity because two other E3 ligases, Pellino1 and Pellino2, could also produce the same Lys63-linked ubiquitin chains produced by TRAF6 which are needed to switch on this process. They also found that the essential roles of TRAF6 are to recruit other proteins into the innate immune signaling network and that this involves a region of the molecule distinct from the RING domain that carries the E3 ligase activity of TRAF6.

In a final unexpected twist to the story, the researchers found that the mice lacking any TRAF6 E3 ligase activity developed multi-organ inflammation within five weeks of birth. These and other observations indicate that an essential role of the TRAF6 E3 ligase is to keep the adaptive immune system in check to prevent autoimmune disease. The Cohen lab is now trying to unravel this novel function of TRAF6.

Sam Strickson, who made many of the key discoveries reported in the paper said:- “our findings came as a great surprise because the E3 ligase activity of TRAF6 has been thought to be so central to all of its functions. Elucidating how the TRAF6 E3 ligase prevents hyper-activation of the adaptive immune system will be exciting, because it may lead to the development of new drugs that can enhance the power of the immune system to destroy the microbes that cause infection and to kill the tumour cells that cause cancer”.