Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 31, Pages 9686-9691Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1503535112
Keywords
inflammation; signaling; endothelial cell; complement; membrane attack complex
Categories
Funding
- National Institutes of Health [R01 HL109455, 5T32A1089704-02, 5T32HL007974-13]
- Merck/American College of Cardiology
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Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-kappa B-inducing kinase (NIK) and activating noncanonical NF-kappa B 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 I kappa B kinase (IKK)-alpha. 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-kappa B by forming a novel Akt(+) NIK+ signalosome on Rab5(+) endosomes.
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