| Autor: |
Fang, Caodi, Manes, Thomas D., Liu, Lufang, Liu, Kevin, Qin, Lingfeng, Li, Guangxin, Tobiasova, Zuzana, Kirkiles-Smith, Nancy C., Patel, Manal, Merola, Jonathan, Fu, Whitney, Liu, Rebecca, Xie, Catherine, Tietjen, Gregory T., Nigrovic, Peter A., Tellides, George, Pober, Jordan S., Jane-wit, Dan |
| Zdroj: |
Nature Communications; 5/21/2019, Vol. 10 Issue 1, pN.PAG-N.PAG, 1p |
| Abstrakt: |
Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that induces non-canonical NF-κB in endothelial cells (EC). In response to membrane attack complexes (MAC), ZFYVE21 is post-translationally stabilized on MAC+Rab5+ endosomes in a Rab5- and PI(3)P-dependent manner. ZFYVE21 promotes SMURF2-mediated polyubiquitinylation and proteasome-dependent degradation of endosome-associated PTEN to induce vesicular enrichment of PI(3,4,5)P3 and sequential recruitment of activated Akt and NF-κB-inducing kinase (NIK). Pharmacologic alteration of cellular phosphoinositide content with miltefosine reduces ZFYVE21 induction, EC activation, and allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC and is detected in human renal and synovial tissues. Our data identifies ZFYVE21 as a Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway in complement-mediated conditions. Complement activation contributes to vascular inflammation in the contexts of allograft rejection and connective tissue disease. Here Fang et al. identify ZFYVE21 as a novel effector of Rab5 and find it regulates pro-inflammatory NF-κB signaling in endothelial cells in response to complement activation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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