FIGURE 1. The well-characterized NF-B signalling pathway, and a new contributor.

a, When ligand (such as tumour-necrosis factor-, TNF-) binds to TNF receptors, the receptors form a trimer and recruit the TRADD protein. b, Subsequently, RIP and TRAFs are recruited. c, The cIAP protein can add a chain of ubiquitin proteins, linked through the amino-acid residue lysine 48, to TRAF2, resulting in its degradation. d, Alternatively, TRAF2 can ubiquitinate itself, using the Ubc13–MMS2 complex, producing a lysine-63-linked ubiquitin chain. (The availability of cIAP, Ubc13 and MMS2 might determine which pathway predominates.) e–g, The IKK kinase complex is recruited (e) and phosphorylates IKK (f); this in turn phosphorylates IB (g), leading to its degradation. NF-B is then free to move into the nucleus and activate target genes. Three new papers^{1, 2, 3} show that the CYLD protein, which is mutated in human cylindromatosis, probably removes lysine-63-linked ubiquitins from TRAF2, thereby preventing further signalling.