ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes

Caodi Fang, Thomas D. Manes, Lufang Liu, Kevin Liu, Lingfeng Qin, Guangxin Li, Zuzana Tobiasova, Nancy C. Kirkiles-Smith, Manal Patel, Jonathan Merola, Whitney Fu, Rebecca Liu, Catherine Xie, Gregory T. Tietjen, Peter A. Nigrovic, George Tellides, Jordan S. Pober and Dan Jane-wit ()
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Caodi Fang: Yale University School of Medicine
Thomas D. Manes: Yale University School of Medicine
Lufang Liu: Yale University School of Medicine
Kevin Liu: Yale University School of Medicine
Lingfeng Qin: Yale University School of Medicine
Guangxin Li: Yale University School of Medicine
Zuzana Tobiasova: Yale University School of Medicine
Nancy C. Kirkiles-Smith: Yale University School of Medicine
Manal Patel: University of Cambridge
Jonathan Merola: Yale University School of Medicine
Whitney Fu: Yale University School of Medicine
Rebecca Liu: Yale University School of Medicine
Catherine Xie: Yale University School of Medicine
Gregory T. Tietjen: Yale University School of Medicine
Peter A. Nigrovic: Boston Children’s Hospital
George Tellides: Yale University School of Medicine
Jordan S. Pober: Yale University School of Medicine
Dan Jane-wit: Yale University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10041-2

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