Proteolysis of the low‐density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases

• Published in: FEBS letters 2023-06, Vol.597 (11), p.1489-1502
• Main Authors: Kellett, Katherine A. B., Fisher, Kate, Aldworth, Harry, Hooper, Nigel M.
• Format: Article
• Language: English
• Subjects: Animals; astacin; BMP1; Bone Morphogenetic Protein 1 - metabolism; Cholesterol; hepatocytes; Hepatocytes - metabolism; Humans; LDL receptor; LDL‐cholesterol; Ligands; Lipoproteins, LDL - metabolism; Liver; Mammals - metabolism; meprin; Metabolism; Mice; Peptide Hydrolases - metabolism; protease; Proteolysis; Receptors, LDL - genetics; Receptors, LDL - metabolism; Sterols
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14667

Bone morphogenetic protein 1 (BMP1), a member of the astacin family of zinc‐metalloproteases, proteolytically cleaves the low‐density lipoprotein receptor (LDLR) within its ligand‐binding domain, reducing the binding and cellular uptake of LDL‐cholesterol. Here, we aimed to determine whether astacin proteases other than BMP1 may also cleave LDLR. Although human hepatocytes express all six astacin proteases, including the meprins and mammalian tolloid, we found through pharmacological inhibition and genetic knockdown that only BMP1 contributed to the cleavage of LDLR in its ligand‐binding domain. We also found that the minimum amino acid change required to render mouse LDLR susceptible to cleavage by BMP1 is mutation at the P1′ and P2 positions of the cleavage site. When expressed in cells, the resulting humanised‐mouse LDLR internalised LDL‐cholesterol. This work provides insight into the biological mechanisms regulating LDLR function. The low‐density lipoprotein receptor (LDLR) binds LDL‐cholesterol at the cell surface and internalises. The protease BMP1 cleaves LDLR in its ligand‐binding domain, preventing the binding and internalisation of LDL‐cholesterol. BMP1 is a member of the astacin family of zinc metalloproteases, however, no other astacin protease, including the meprins, is involved in cleaving LDLR in human hepatocytes.