Tarantino et al. identify molecular clusters that help cells switch on the transcription factor NF-κB.
NF-κB controls processes as diverse as immune responses, cell growth, and apoptosis. Cells normally keep NF-κB under wraps in the cytoplasm, but the IKK complex removes this inhibition, enabling NF-κB to enter the nucleus. The on–off switch for the IKK complex is the NEMO subunit. NEMO activation depends on its binding to two types of ubiquitin chains: K63 chains, in which ubiquitin molecules link through their lysine at position 63; and linear chains, in which the ubiquitins link through their N-terminal methionine. Recent results suggest that the activation of NEMO and NF-κB by different inflammation-promoting cytokines requires different patterns of ubiquitin chain formation.
Tarantino et al. tested this possibility by tracking NEMO’s movements in cells stimulated by IL-1 or TNF. Both cytokines spurred NEMO subunits to join large clumps of molecules at the cell membrane. These structures were rich in active IKK complexes, suggesting that their formation helps switch on IKK.
The researchers uncovered several differences between the IKK-containing structures triggered by the two cytokines. The clusters induced by TNF cozy up to the TNF receptor, but the structures spurred by IL-1 don’t associate with the IL-1 receptor. Formation of IL-1–induced structures required K63 and linear ubiquitination, whereas TNF-induced clusters appeared in the absence of either type of ubiquitination. The results suggest that directing NEMO into large—but distinct—clusters enables cells to activate NF-κB in response to TNF and IL-1. Disassembly of the structures, possibly by removal of ubiquitins, might enable cells to quickly shut off NF-κB’s activity.