Editors' ChoiceImmunology

Separate Roles

Science Signaling  23 Feb 2010:
Vol. 3, Issue 110, pp. ec61
DOI: 10.1126/scisignal.3110ec61

In addition to their functions in mediating immune responses, nuclear factor κB (NF-κB) transcription factors are also important in development. NF-κB subunits are sequestered in the cytoplasm in a complex with inhibitor of NF-κB (IκB) proteins, which are targeted for degradation after their phosphorylation by the IκB kinase (IKK) complex. IKK consists of catalytic subunits and the regulatory subunit IKKγ (also known as NEMO), which is encoded by the X-linked gene Ikbkg. Deletion of Ikbkg in males is lethal, whereas males with hypomorphic mutations in Ikbkg survive, albeit often with combined immune deficiency and ectodermal abnormalities. Siggs et al. used chemical mutagenesis to generate a strain of mice called pan-resistance 2 (panr2), which had a point mutation in Ikbkg. Unlike Ikbkg hypomorphs, these mice had impaired immune responses but normal development of the skin. The point mutation in Ikbkg resulted in a single amino acid substitution in NEMO that did not affect its abundance. Biochemical experiments demonstrated that, although p38 mitogen-activated protein kinase (MAPK) was activated normally in response to Toll-like receptor (TLR) agonists in macrophages from panr2 mice, phosphorylation of the MAPK extracellular signal–regulated kinase (ERK) and the p105 NF-κB protein was impaired. Although degradation of IκBα was normal in panr2 macrophages, nuclear translocation of p65 NF-κB was defective. In addition to highlighting immunological responses of NEMO that are independent of its targeting of IκB proteins for degradation, the generation of panr2 mice has demonstrated a mutation in Ikbkg that impairs its immune, but not developmental, functions.

O. M. Siggs, M. Berger, P. Krebs, C. N. Arnold, C. Eidenschenk, C. Huber, E. Pirie, N. G. Smart, K. Khovananth, Y. Xia, G. McInerney, G. B. Karlsson Hedestam, D. Nemazee, B. Beutler, A mutation of Ikbkg causes immune deficiency without impairing degradation of IκBα. Proc. Natl. Acad. Sci. U.S.A. 107, 3046–3051 (2010). [Abstract] [Full Text]