Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a soluble protein that directs membrane-bound receptors to lysosomes for degradation. In the most studied example of this, PCSK9 binding leads to the degradation of low density lipoprotein receptor (LDLR), significantly affecting circulating LDL-C levels. The mechanism mediating this degradation, however, is not completely understood. We show here that LDLR facilitates PCSK9 interactions with amyloid precursor like protein 2 (APLP2) at neutral pH leading to PCSK9 internalization, although direct binding between PCSK9 and LDLR is not required. Moreover, binding to APLP2 or LDLR is independently sufficient for PCSK9 endocytosis in hepatocytes, while LDL can compete with APLP2 for PCSK9 binding to indirectly mediate PCSK9 endocytosis. Finally, we show that APLP2 and LDLR are also required for the degradation of another PCSK9 target, APOER2, necessitating a general role for LDLR and APLP2 in PCSK9 function. Together, these findings provide evidence that PCSK9 has at least two endocytic epitopes that are utilized by a variety of internalization mechanisms and clarifies how PCSK9 may direct proteins to lysosomes.
Highlights
High serum LDL-cholesterol (LDL-C) levels correlate strongly with hypercholesterolemia and coronary artery disease (CAD)
Numerous reports in the literature have shown that LDL receptor (LDLR) mediates Proprotein convertase subtilisin/kexin type 9 (PCSK9) endocytosis [25, 26]
While we showed novel interactions between PCSK9 and amyloid precursor protein (APP) or amyloid precursor like protein 2 (APLP2), our data indicated that neither of these interactions was required for PCSK9 endocytosis
Summary
High serum LDL-cholesterol (LDL-C) levels correlate strongly with hypercholesterolemia and coronary artery disease (CAD). Multitudes of CAD prevention therapeutics focus on lowering LDL-C levels One such approach aims to increase expression of the LDL receptor (LDLR), a protein that clears LDL-C from the blood. LDL binds LDLR on the cell surface, and following internalization, LDLR undergoes a pH-dependent conformational change upon entering endosomes. This causes LDLR to release bound LDL which is delivered to lysosomes, while LDLR itself is recycled back to the cell surface to repeat the process [1]. The CHRD interacts in a pH dependent manner with APLP2, a member of the amyloid precursor protein (APP) family This interaction allows PCSK9 to bridge LDLR to APLP2, which in turn transports the entire complex to lysosomes [14]. We sought to elucidate the mechanism(s) of PCSK9 internalization that are independent of direct LDLR binding in hepatic cells
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