NEDD4 protects vascular endothelial cells against Angiotensin II-induced cell death via enhancement of XPO1-mediated nuclear export

Jianning Xu; Zhiyong Sheng; Fuxin Li; Shu Wang; Ying Yuan; Meng Wang; Zhihong Yu

doi:10.1016/j.yexcr.2019.111505

NEDD4 protects vascular endothelial cells against Angiotensin II-induced cell death via enhancement of XPO1-mediated nuclear export

Exp Cell Res. 2019 Oct 1;383(1):111505. doi: 10.1016/j.yexcr.2019.111505. Epub 2019 Jul 19.

Authors

Jianning Xu¹, Zhiyong Sheng¹, Fuxin Li¹, Shu Wang¹, Ying Yuan¹, Meng Wang¹, Zhihong Yu²

Affiliations

¹ Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
² Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China. Electronic address: yuzhihong86@sina.com.

PMID: 31326389
DOI: 10.1016/j.yexcr.2019.111505

Abstract

NEDD4 is an E3 ubiquitin ligase containing the HECT domain, which regulates various cellular processes, but its role in vascular endothelial cells is unknown. In the present study, we found that NEDD4 bound directly to XPO1 by co-immunoprecipitation screening. In HUVECs (human umbilical vein endothelial cells), overexpression of NEDD4 reduced Ang II-induced ROS level and cell apoptosis. Ang II stimulation led to nuclear accumulation of cargoes, while overexpression of NEDD4 enhanced the XPO1-dependent nuclear export of its cargoes. KPT185, an inhibitor of XPO1, can abolished the protective effect of NEDD4 under Ang II treatment. In addition, NEDD4 could promote the interaction between XPO1 and RanBP3 via K63-linked ubiquitination of XPO1. These results suggested that NEDD4 played a protective role in vascular endothelial cell injury through regulating XPO1-mediated nuclear export.

Keywords: NEDD4; Nuclear expor; Ubiquitination; XPO1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / drug effects*
Angiotensin II / pharmacology*
Apoptosis / drug effects*
Exportin 1 Protein
Human Umbilical Vein Endothelial Cells / drug effects*
Human Umbilical Vein Endothelial Cells / metabolism
Human Umbilical Vein Endothelial Cells / pathology
Humans
Karyopherins / genetics
Karyopherins / metabolism*
Nedd4 Ubiquitin Protein Ligases / genetics
Nedd4 Ubiquitin Protein Ligases / metabolism*
Protective Agents / metabolism*
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Ubiquitination
Vasoconstrictor Agents / pharmacology

Substances

Karyopherins
Protective Agents
Receptors, Cytoplasmic and Nuclear
Vasoconstrictor Agents
Angiotensin II
Nedd4 Ubiquitin Protein Ligases
Nedd4 protein, human