Endosome-Based Activation of Non-Canonical NF-kB Signaling By Membrane Attack Complexes
1Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT
2Yale Center for Molecular Discovery, Yale University School of Medicine, New Haven, CT
3Department of Surgery, Yale University School of Medicine, New Haven, CT
4Department of Immunobiology, Yale University School of Medicine, New Haven, CT
5Department of Pathology, Yale University School of Medicine, New Haven, CT.
Meeting: 2015 American Transplant Congress
Abstract number: C291
Keywords: Alloantibodies, Graft arterlosclerosis, Nuclear factor-kappa B (NF-kB), Rejection
Session Information
Session Name: Poster Session C: Late Breaking
Session Type: Poster Session
Date: Monday, May 4, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Using sera from transplant patients with high-titer panel reactive antibody (PRA), we previously described a model for studying the effects of alloantibody binding and complement activation on human endothelial cells (EC). With this model we found that complement membrane attack complexes (MAC) induced rapid post-translational stabilization of NF-kB-inducing kinase (NIK), the activator of non-canonical NF-kB signaling, which was required for inflammatory changes in cultured human EC and for vasculopathic changes in human coronary artery segments implanted into immunodeficient mouse hosts. To elucidate the mechanism of NIK stabilization, we performed a genome-wide siRNA screen and discovered a novel, TRAF3-independent signaling mechanism in which MAC induces NIK stabilization on endosomes. MAC is internalized by EC in a clathrin-, AP2-, and dynamin-dependent mechanism into Rab5+ endosomes. Activated Akt is recruited in a Rab5-dependent manner to the same endosomes which then bind and stabilize NIK and subsequently recruit and activate IKK-alpha, the catalytic activator of p52/RelB complexes, the non-canonical form of NF-kB. Pharmacological inhibition of MAC endocytosis blocked this pathway both in cultured EC and in human coronary artery xenografts. These data reveal a novel endosome-based signaling cascade for activating non-canonical NF-kB and identify new targets for inhibiting complement-mediated tissue injury such as chronic antibody-mediated rejection and cardiac allograft vasculopathy.
To cite this abstract in AMA style:
Jane-wit D, Surovtseva Y, Qin L, Clark P, Manes T, Kashgarian M, Kirkiles-Smith N, Liu R, Wang C, Tellides G, Pober J. Endosome-Based Activation of Non-Canonical NF-kB Signaling By Membrane Attack Complexes [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/endosome-based-activation-of-non-canonical-nf-kb-signaling-by-membrane-attack-complexes/. Accessed October 9, 2024.« Back to 2015 American Transplant Congress