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Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9686-91. doi: 10.1073/pnas.1503535112. Epub 2015 Jul 20.

Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes.

Author information

1
Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520;
2
Yale Center for Molecular Discovery, Yale University, New Haven, CT 06516;
3
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520;
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
5
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
6
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520 jordan.pober@yale.edu.

Abstract

Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-κB-inducing kinase (NIK) and activating noncanonical NF-κB signaling. Here we report a novel endosome-based signaling complex induced by MACs to stabilize NIK. We found that, 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-dependent manner 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. We conclude that MACs activate noncanonical NF-κB by forming a novel Akt(+)NIK(+) signalosome on Rab5(+) endosomes.

KEYWORDS:

complement; endothelial cell; inflammation; membrane attack complex; signaling

PMID:
26195760
PMCID:
PMC4534258
DOI:
10.1073/pnas.1503535112
[Indexed for MEDLINE]
Free PMC Article

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