Editors' ChoiceImmunology

Will the Real NIK Function Please Stand Up?

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Science's STKE  27 Feb 2001:
Vol. 2001, Issue 71, pp. tw4
DOI: 10.1126/stke.2001.71.tw4

The nuclear factor-κB (NF-κB)-inducing kinase (NIK) was originally identified as a MAP kinase kinase kinase (MAPKKK, MEKK) that phosphorylated IκB kinase (IKK) α and activated NF-κB. Subsequently, NIK-deficient mouse studies revealed that NIK is not essential for cytokine-dependent IKK activiation. A naturally occurring NIK gene mutation results in alymphoplasia (aly) in mice, which leads to defective antibody responses, and the aly phenotype resembles the nfkb2-deficient phenotype. The 100-kD NFkB2 precursor protein is cleaved to a mature 52-kD protein that heterodimerizes with Rel proteins members of the NF-κB family to form a functional transcription factor. Overexpression of NIK and p100 in different cell lines promoted the accumulation of mature p52 protein, suggesting a role for NIK in the processing of p100. The presence of p52 required the kinase activity of NIK, was independent of IKK phosphorylation, and was blocked by proteasomal inhibitors. NIK phosphorylation of p100 at Ser866 and Ser870 was essential for the subsequent ubiquitination of p100 and processing to p52. Assays done with NIK from aly-/- and aly-/+ mice revealed that the amounts of NFkB2 proteins were the same but that p52 was barely detectable in aly-/- cells. Additionally, cells overexpressing the NIK aly allele were completely defective for p100 processing. Thus, the real function of NIK may be to regulate the maturation of p52, instead of activating NF-κB from inactive cytoplasmic complexes.

G. Xiao, E. W. Harhaj, S.-C. Sun, NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401-409 (2001). [Online Journal]

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