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

• DOI: 10.1073/pnas.1503535112
• Publication Date: 2015-07-21T00:23:40Z
• Authors: Dan Jane-wit; Yulia V. Surovtseva; Lingfeng Qin; Guangxin Li; Rebecca Liu; Pamela Clark; Thomas D. Manes; Chen Wang; Michael Kashgarian; Nancy C. Kirkiles...; George Tellides; Jordan S. Pober
• Keywords: 0303 health sciences; Secretory Vesicles; Hydrazones; NF-kappa B; Complement Membrane Attack Complex; Endosomes; Mice, SCID; Protein Serine-Threonine Kinases; Flow Cytometry; Coronary Vessels; Baculoviral IAP Repeat-Containing 3 Protein; Clathrin; Endocytosis; Inhibitor of Apoptosis Proteins; 03 medical and health sciences; Protein Biosynthesis; Enzyme Stability; Human Umbilical Vein Endothelial Cells; Animals; Humans; RNA, Small Interfering; Proto-Oncogene Proteins c-akt

Significance

Complement activation contributes to host defense and immunopathology. We recently discovered that membrane attack complexes (MAC), the terminal effector mechanisms of complement, activate proinflammatory functions in human endothelial cells (ECs) via noncanonical NF-ΚB signaling. Here we elucidate the initial steps of how MACs activate this pathway. MACs formed on the surface of human ECs are rapidly internalized via clathrin-mediated endocytosis into Rab5 + endosomes, which subsequently recruit activated Akt in a Rab5-dependent manner. Akt recruitment results in NIK protein stabilization on the surface of the endosome within 30 min, initiating noncanonical NF-ΚB signaling. MAC internalization in ECs lining human coronary arteries in vivo similarly activates noncanonical NF-ΚB signaling. Our findings suggest new therapeutic targets for controlling complement-mediated inflammation.