TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Mice lacking TRAF6 exhibit impaired bone resorption and tooth eruption due to defective osteoclast function. In vitro studies show that TRAF6 is crucial for IL-1 and CD40 signaling, as well as for LPS signaling. TRAF6 is essential for perinatal and postnatal survival, highlighting its critical role in both immune system regulation and bone metabolism. These findings reveal diverse and critical functions of TRAF6 in various physiological processes.TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Mice lacking TRAF6 exhibit impaired bone resorption and tooth eruption due to defective osteoclast function. In vitro studies show that TRAF6 is crucial for IL-1 and CD40 signaling, as well as for LPS signaling. TRAF6 is essential for perinatal and postnatal survival, highlighting its critical role in both immune system regulation and bone metabolism. These findings reveal diverse and critical functions of TRAF6 in various physiological processes.