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.