Research Departments & Organizations
Using sera from transplant patients to study the effects of complement, a set of circulating pro-inflammatory immune proteins involved in transplant rejection, we have identified a novel complement-mediated effector pathway, non-canonical NF-kB in endothelial cells (EC). This pathway activated a broad range of inflammatory molecules in EC and potentiated the ability of EC to activate alloimmune CD4+ T cells. Non-canonical NF-kB activation was detected in cultured human EC, in human coronary artery xenografts implanted in immunodeficient mice, and in biopsy specimens from five different patient cohorts with systemic complement activation. As such, inhibition of this pathway may have clinical implications for a broad number of complement-mediated conditions including transplant rejection and connective tissue disorders like lupus and rheumatoid arthritis.
Using a genome-wide siRNA screen, we have found that non-canonical NF-kB activation by complement occurs entirely intracellularly on Rab5+ vesicles which, following complement treatment, become a signaling platform that recruits signaling components that are entirely distinct from those in described pathways of non-canonical NF-kB activation via ligand:receptor interactions.
Our current areas of research include: 1) determining endosome-associated signaling components(s) required for complement to activate non-canonical NF-kB, 2) identifying how non-canonical NF-kB initiates downstream pro-inflammatory pathway(s) including inflammasome assembly, and 3) understanding how complement-treated endothelial cells potentiate alloimmune CD4+ T cell activation. We have a number of ongoing translational projects in each of these areas that are very exciting. Please do not hesitate to contact me to speak if you have an interest in any of the above.
ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes.
Fang C, Manes TD, Liu L, Liu K, Qin L, Li G, Tobiasova Z, Kirkiles-Smith NC, Patel M, Merola J, Fu W, Liu R, Xie C, Tietjen GT, Nigrovic PA, Tellides G, Pober JS, Jane-Wit D. ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes. Nat Commun 2019, 10:2247. 2019
Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes.
Jane-wit D, Surovtseva YV, Qin L, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles-Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112:9686-91. 2015
Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-κB signaling in endothelial cells.
Jane-Wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, Abrahimi P, Devalliere J, Moeckel G, Kulkarni S, Tellides G, Pober JS. Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-κB signaling in endothelial cells. Circulation 2013, 128:2504-16. 2013