title: Common Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Epitopes Mediate Multiple Routes for Internalization and Function.
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.
authors.affiliation: Rinat-Pfizer Inc., South San Francisco, California, United States of America.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: DeVay
authors.affiliation: Rinat-Pfizer Inc., South San Francisco, California, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Yamamoto
authors.affiliation: Rinat-Pfizer Inc., South San Francisco, California, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Shelton
authors.affiliation: Rinat-Pfizer Inc., South San Francisco, California, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis; D000939:Epitopes / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; D026502:LDL-Receptor Related Proteins; C573412:LDLR protein, human; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; C098773:low density lipoprotein receptor-related protein 8; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases