Keeping NF-κB in check

NF-κB, a central proinflammatory regulator, gets activated by TNF receptor–associated factors (TRAFs). But He et al. (page 2413) now report that one TRAF family member (TRAF3) instead negatively regulates an alternative NF-κB activation pathway.

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

It was known that, unlike other TRAFs, overexpression of TRAF3 does not induce the classical NF-κB 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-κB. This constitutive activation was associated with aberrant accumulation of NIK protein, but not...