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CD40-induced nuclear accumulation of NF-B (green) is blocked by NEMO mutations.

A wide variety of inflammatory stimuli trigger the activation of IB kinase (IKK), the enzyme complex that activates the NF-B transcription factors. But all NF-B–inducing signals are not the same, according to Filipe-Santos and colleagues (page 1745), who identify mutations in the regulatory subunit of IKK that selectively disarm just one of these pathways.

Most NF-B–inducing stimuli, including byproducts of microbial infection and inflammatory cytokines, trigger the phosphorylation of the and ß subunits of IKK. Heterodimers of IKK and ß then bind to IKK (or NEMO)—the regulatory subunit of the complex. Thus assembled, this protein complex phosphorylates the NF-B inhibitor proteins (IBs), tagging it for proteasomal degradation and freeing NF-B 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-B–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.

hvanepps{at}rockefeller.edu

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X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production

Orchidée Filipe-Santos, Jacinta Bustamante, Margje H. Haverkamp, Emilie Vinolo, Cheng-Lung Ku, Anne Puel, David M. Frucht, Karin Christel, Horst von Bernuth, Emmanuelle Jouanguy, Jacqueline Feinberg, Anne Durandy, Brigitte Senechal, Ariane Chapgier, Guillaume Vogt, Ludovic de Beaucoudrey, Claire Fieschi, Capucine Picard, Meriem Garfa, Jalel Chemli, Mohamed Bejaoui, Maria N. Tsolia, Necil Kutukculer, Alessandro Plebani, Luigi Notarangelo, Christine Bodemer, Frédéric Geissmann, Alain Israël, Michel Véron, Maike Knackstedt, Ridha Barbouche, Laurent Abel, Klaus Magdorf, Dominique Gendrel, Fabrice Agou, Steven M. Holland, and Jean-Laurent Casanova
J. Exp. Med. 2006 203: 1745-1759. [Abstract] [Full Text] [PDF]

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