MMP-2 inhibits PCSK9-induced degradation of the LDL receptor in Hepa1-c1c7 cells

Xiang Wang; Evan Berry; Samuel Hernandez-Anzaldo; Difei Sun; Ayinuer Adijiang; Liang Li; Dawei Zhang; Carlos Fernandez-Patron

doi:10.1016/j.febslet.2015.01.007

MMP-2 inhibits PCSK9-induced degradation of the LDL receptor in Hepa1-c1c7 cells

FEBS Lett. 2015 Feb 13;589(4):490-6. doi: 10.1016/j.febslet.2015.01.007. Epub 2015 Jan 19.

Authors

Xiang Wang¹, Evan Berry¹, Samuel Hernandez-Anzaldo¹, Difei Sun², Ayinuer Adijiang³, Liang Li², Dawei Zhang⁴, Carlos Fernandez-Patron⁵

Affiliations

¹ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
² Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada; Faculty of Science, University of Alberta, Edmonton, Alberta, Canada.
³ Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁴ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada; Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: cf2@ualberta.ca.

PMID: 25613181
DOI: 10.1016/j.febslet.2015.01.007

Abstract

Low-density lipoprotein receptor (LDLR) catalyzes the uptake of LDL-cholesterol by liver and peripheral organs. The function of the LDLR is antagonized by pro-protein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR at the plasma membrane inducing LDLR degradation. Here, we report that matrix metalloproteinase-2 (MMP-2) interacts with and cleaves PCSK9, as evidenced by proteomic, chemical cross-linkage, blue native-PAGE and domain-specific antibodies Western blot analyses. Furthermore, MMP-2 overexpression renders Hepa1-c1c7 cells resistant to PCSK9-induced LDLR degradation. The data suggest that pathological MMP-2 overexpression may protect the LDLR from PCSK-9-induced degradation.

Keywords: Atherosclerosis; Cholesterol; Low density lipoprotein receptor; Matrix metalloproteinase-2; Pro-protein convertase subtilisin/kexin type 9; Sterol-regulatory element binding protein.

Publication types

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

MeSH terms

Amino Acid Sequence
Animals
Cell Line
Matrix Metalloproteinase 2 / physiology*
Mice
Molecular Sequence Data
Proprotein Convertase 9
Proprotein Convertases / physiology*
Proteolysis
Receptors, LDL / metabolism*
Serine Endopeptidases / physiology*

Substances

Receptors, LDL
Pcsk9 protein, mouse
Proprotein Convertase 9
Proprotein Convertases
Serine Endopeptidases
Matrix Metalloproteinase 2
Mmp2 protein, mouse

Grants and funding

RES0011328/Canadian Institutes of Health Research/Canada