| First Author | Susan-Resiga D | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 4 | Pages | 101177 |
| PubMed ID | 34508778 | Mgi Jnum | J:312366 |
| Mgi Id | MGI:6787340 | Doi | 10.1016/j.jbc.2021.101177 |
| Citation | Susan-Resiga D, et al. (2021) Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin. J Biol Chem 297(4):101177 |
| abstractText | The hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote carriers of ASGR1 deletions exhibit approximately 34% lower risk of coronary artery disease and approximately 10% to 14% reduction of non-HDL cholesterol. Since the proprotein convertase PCSK9 is a major degrader of the low-density lipoprotein receptor (LDLR), we investigated the degradation and functionality of LDLR and/or PCSK9 by endogenous/overexpressed ASGR1 using Western blot and immunofluorescence in HepG2-naive and HepG2-PCSK9-knockout cells. ASGR1, like PCSK9, targets LDLR, and both independently interact with/enhance the degradation of the receptor. This lack of cooperativity between PCSK9 and ASGR1 was confirmed in livers of wildtype (WT) and Pcsk9(-/-) mice. ASGR1 knockdown in HepG2-naive cells significantly increased total ( approximately 1.2-fold) and cell-surface ( approximately 4-fold) LDLR protein. In HepG2-PCSK9-knockout cells, ASGR1 silencing led to approximately 2-fold higher levels of LDLR protein and DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate)-LDL uptake associated with approximately 9-fold increased cell-surface LDLR. Overexpression of WT-ASGR1/2 primarily reduced levels of immature non-O-glycosylated LDLR ( approximately 110 kDa), whereas the triple Ala-mutant of Gln240/Trp244/Glu253 (characterized by loss of carbohydrate binding) reduced expression of the mature form of LDLR ( approximately 150 kDa), suggesting that ASGR1 binds the LDLR in both a sugar-dependent and -independent fashion. The protease furin cleaves ASGR1 at the RKMK(103) downward arrow motif into a secreted form, likely resulting in a loss of function on LDLR. Altogether, we demonstrate that LDLR is the first example of a liver-receptor ligand of ASGR1. We conclude that silencing of ASGR1 and PCSK9 may lead to higher LDL uptake by hepatocytes, thereby providing a novel approach to further reduce LDL cholesterol levels. |
