Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling

TRAF6 is essential for many biological processes, including the operation of the innate immune system and bone formation. The enzymatic activity of TRAF6, an E3 ubiquitin ligase, is thought to have a pivotal role in triggering these processes. In this paper, we reexamined this assumption by generating mice expressing a catalytically inactive mutant of TRAF6. The bone structure of the mice was normal and a major intracellular signaling pathway of the immune system could still be switched on. We found that other E3 ligases, Pellino1 and Pellino2, could generate the ubiquitin chains needed to switch on immune signaling in human cells expressing catalytically inactive TRAF6. Our findings identify essential roles of TRAF6 that are independent of its enzymatic activity.