Globotriaosylceramide induces lysosomal degradation of endothelial K Ca3.1 in fabry disease

Shinkyu Choi, Ji Aee Kim, Hye Young Na, Sung Eun Cho, Seonghee Park, Sung Chul Jung, Suk Hyo Suh

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

OBJECTIVE - Globotriaosylceramide (Gb3) induces KCa3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces K Ca3.1 endocytosis and degradation. APPROACH AND RESULTS - K Ca3.1, especially plasma membrane-localized KCa3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced KCa3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress-inducing agents did not induce K Ca3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged α-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated KCa3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered KCa3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored KCa3.1 expression, the current, and endothelium-dependent relaxation. CONCLUSIONS: - Gb3 accelerates the endocytosis and lysosomal degradation of endothelial KCa3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD.

Original languageEnglish
Pages (from-to)81-89
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Ca-activated K channels
  • Fabry disease
  • Glycosphingolipids
  • Protein transport

Fingerprint

Dive into the research topics of 'Globotriaosylceramide induces lysosomal degradation of endothelial K Ca3.1 in fabry disease'. Together they form a unique fingerprint.

Cite this