1745), who identify mutations in the regulatory subunit of IKK that selectively disarm just one of these pathways.
Most NF-κB–inducing stimuli, including byproducts of microbial infection and inflammatory cytokines, trigger the phosphorylation of the α and β subunits of IKK. Heterodimers of IKKα and β then bind to IKKγ (or NEMO)—the regulatory subunit of the complex. Thus assembled, this protein complex phosphorylates the NF-κB inhibitor proteins (IκBs), tagging it for proteasomal degradation and freeing NF-κB for translocation into the nucleus.
Here, Filipe-Santos et al. identify two point mutations in NEMO in patients with an X-linked susceptibility to mycobacterial infection. These mutations blocked the NF-κB–driven production of interleukin (IL)-12 by monocytes and dendritic cells (DCs). But this block occurred only in response to T cell–based signals, triggered by the interaction between CD40 ligand (on activated T cells) and its partner CD40 (on monocytes and DCs). IL-12 production in response to other IKK-inducing stimuli (including bacterial LPS and live mycobacteria) was unaffected.
It is unclear why these NEMO mutations, both in the protein's leucine zipper (LZ) domain, preferentially affect CD40-induced signals. One possibility is that NEMO interacts with distinct IKK-activating kinases depending on the upstream signal, and the LZ domain is required for NEMO to latch on to a specific CD40-triggered kinase.
From the disease standpoint, it makes sense that IL-12-blocking NEMO mutations predispose people to mycobacterial infection, as IL-12 is known to be essential for defending against mycobacteria. Monocytes infected with mycobacteria themselves produce IL-12, but these data suggest that infection-induced IL-12 is not enough to control the growth of the bug. Perhaps the amount of IL-12 is simply too low unless T cells get in on the act.