Hu & Zhang Lab
The State Key Laboratory of Biotherapy Si-Chuan University

Activation of non-canonical NF-kB by Akt-NIK

Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-κBinducing kinase (NIK) and activating noncanonical NF-κB signaling.

Dan JAne-Wit et al reported a novel endosome-based signaling complex induced by MACs to stabilize NIK. In contrast to cytokine-mediated activation, NIK stabilization by MACs did not involve cIAP2 or TRAF3. Informed by a genome-wide siRNA screen, instead this response required internalization of MACs in a clathrin-,AP2-, and dynamin-dependentmanner into Rab5+endosomes,which recruited activated Akt, stabilized NIK, and led to phosphorylation of IκB kinase (IKK)-α. Active Rab5 was required for recruitment of activated Akt to MAC+ endosomes, but not for MAC internalization or for Akt activation. Consistent with these in vitro observations, MAC internalization occurred in human coronary ECs in vivo and was similarly required for NIK stabilization and EC activation. MACs activate noncanonical NF-κB by forming a novel Akt+NIK+ signalosome on Rab5+ endosomes.

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