Cells lacking TRAF3 constitutively release active p52 NF-B.

Classical activation of NF-B occurs by TRAF-controlled degradation of cytoplasmic inhibitory binding proteins, which leads to nuclear accumulation of the p50 forms of NF-B. Activation can also occur by a recently discovered route requiring NF-B–inducing kinase (NIK), which releases a different NF-B complex, thus one containing p52.

It was known that, unlike other TRAFs, overexpression of TRAF3 does not induce the classical NF-B pathway. By examining TRAF3-null mice (which die soon after birth), He et al. now show that cells from these mice have constitutively active noncanonical p52 NF-B. This constitutive activation was associated with aberrant accumulation of NIK protein, but not mRNA, suggesting that TRAF3 blocks noncanonical NF-B by reducing NIK protein stability.

Crossing the TRAF3^–/– mice with mice that lacked p52 prevented their early death, showing that overactivity of p52 was, indeed, the cause of lethality. The final cause of death in TRAF3^–/– mice is uncertain but is most likely due to over-inflammation caused by the unfettered activation of NF-B-signaling.