Dataset Information

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

ABSTRACT: Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that regulates pro-inflammatory non-canonical NF-B signaling in endothelial cells (EC). In response to membrane attack complexes (MAC), 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-B-inducing kinase (NIK). Pharmacologic alteration of the phosphoinositide content of MAC+Rab5+ endosomes with miltefosine reduces ZFYVE21 induction, EC activation, as well as allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC- but not ligand-induced non-canonical NF-B and is a biomarker for complement-mediated endothelial signaling in human renal and synovial tissues. 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 complement-mediated pathologies.

INSTRUMENT(S): 6520 Quadrupole Time-of-Flight LC/MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Blood Vessel Endothelial Progenitor Cell, Cell Culture

DISEASE(S): Myocardial Ischemia

SUBMITTER: Caodi Fang

LAB HEAD: Dan Jane-wit

PROVIDER: PXD013381 | Pride | 2019-04-09

REPOSITORIES: Pride

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

Fang Caodi C Manes Thomas D TD Liu Lufang L Liu Kevin K Qin Lingfeng L Li Guangxin G Tobiasova Zuzana Z Kirkiles-Smith Nancy C NC Patel Manal M Merola Jonathan J Fu Whitney W Liu Rebecca R Xie Catherine C Tietjen Gregory T GT Nigrovic Peter A PA Tellides George G Pober Jordan S JS Jane-Wit Dan D

Nature communications 20190521 1

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 ...[more]

PMID: 31113953

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