ZFYVE21 is a Novel Complement-Induced Rab5 Effector Protein Mediating Cardiac Allograft Vasculopathy
1Dept of Cardiology, Yale University School of Medicine, New Haven, CT, 2Dept of Rheumatology, Immunology, and Allergy, Harvard University, Boston, MA, 3Dept of Surgery, Yale University School of Medicine, New Haven, CT, 4Dept of Immunobiology, Yale University School of Medicine, New Haven, CT
Meeting: 2019 American Transplant Congress
Abstract number: 69
Keywords: Alloantibodies, Endothelial activation, Inflammation, T cell activation
Session Information
Session Name: Concurrent Session: Endothelial Cell Biology
Session Type: Concurrent Session
Date: Sunday, June 2, 2019
Session Time: 2:30pm-4:00pm
Presentation Time: 2:42pm-2:54pm
Location: Room 310
*Purpose: Complement promotes vascular inflammation in transplant organ rejection, a process leading to cardiac allograft vasculopathy. In this study, we identify a new Rab5 effector protein, ZFYVE21, that mediates this process. We elucidate a ZFYVE21-SMURF2-pAkt signaling axis which activates non-canonical NF-kB, and we explore the clinical relevance of this sequence.
*Methods: We developed FACS-assisted protocols enabling proteomic analysis of MAC+Rab5+ endosomes and semi-quantitative analyses of the phosphoinositide content of these structures. A humanized mouse model incorporating human coronary artery segments and human lymphoid cells was employed to define a role for ZFYVE21-associated signaling in cardiac allograft vasculopathy. Software-assisted analyses of human transplant biopsies analyzing ZFYVE21 colocalization was performed using a computer algorithm we helped to developed in-house.
*Results: In response to deposition of membrane attack complexes (MAC) on endothelial cells (EC), ZFYVE21 is post-translationally stabilized via recruitment to 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 the phosphoinositide content of MAC+Rab5+ endosomes with miltefosine reduces ZFYVE21 induction, EC activation, and MAC-induced allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC- but not ligand-induced non-canonical NF-κB and is a biomarker for complement-mediated endothelial signaling in transplant biopsies with antibody-mediated rejection.
*Conclusions: Our data identifies ZFYVE21 as a novel Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway as a drug target and biomarker for allograft vasculopathy.
To cite this abstract in AMA style:
Jane-wit D, Fang C, Liu L, Qin L, Li GGuangxin, Nigrovic P, Tellides G, Pober J. ZFYVE21 is a Novel Complement-Induced Rab5 Effector Protein Mediating Cardiac Allograft Vasculopathy [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/zfyve21-is-a-novel-complement-induced-rab5-effector-protein-mediating-cardiac-allograft-vasculopathy/. Accessed May 9, 2025.« Back to 2019 American Transplant Congress