Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake

Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the LDL receptor (LDLR) for degradation, increasing plasma LDL and, consequently, cardiovascular risk. Uptake of secreted PCSK9 is required for its effect on the LDLR, and LDL itself inhibits this uptake, though how it does so remains unclear. In this study, we investigated the relationship between LDL, the PCSK9:LDLR interaction, and PCSK9 uptake. We show that LDL inhibits binding of PCSK9 to the LDLR in vitro more impressively than it inhibits PCSK9 uptake in cells. Furthermore, cell-surface heparin-like molecules (HLMs) can partly explain this difference, consistent with heparan sulfate proteoglycans (HSPGs) acting as coreceptors for PCSK9. We also show that HLMs can interact with either PCSK9 or LDL to modulate the inhibitory activity of LDL on PCSK9 uptake, with such inhibition rescued by competition with the entire PCSK9 prodomain, but not its truncated variants. Additionally, we show that the gain-of-function PCSK9 variant, S127R, located in the prodomain near the HSPG binding site, exhibits increased affinity for HLMs, potentially explaining its phenotype. Overall, our findings suggest a model where LDL acts as a negative regulator of PCSK9 function by decreasing its uptake via direct interactions with either the LDLR or HLMs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the LDL receptor (LDLR) for degradation, increasing plasma LDL and, consequently, cardiovascular risk. Uptake of secreted PCSK9 is required for its effect on the LDLR, and LDL itself inhibits this uptake, though how it does so remains unclear. In this study, we investigated the relationship between LDL, the PCSK9:LDLR interaction, and PCSK9 uptake. We show that LDL inhibits binding of PCSK9 to the LDLR in vitro more impressively than it inhibits PCSK9 uptake in cells. Furthermore, cell-surface heparin-like molecules (HLMs) can partly explain this difference, consistent with heparan sulfate proteoglycans (HSPGs) acting as coreceptors for PCSK9. We also show that HLMs can interact with either PCSK9 or LDL to modulate the inhibitory activity of LDL on PCSK9 uptake, with such inhibition rescued by competition with the entire PCSK9 prodomain, but not its truncated variants. Additionally, we show that the gain-of-function PCSK9 variant, S127R, located in the prodomain near the HSPG binding site, exhibits increased affinity for HLMs, potentially explaining its phenotype. Overall, our findings suggest a model where LDL acts as a negative regulator of PCSK9 function by decreasing its uptake via direct interactions with either the LDLR or HLMs. Gain-of-function (GOF) mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, which encodes a self-cleaving protease, cause autosomal dominant familial hypercholesterolemia (1Abifadel M. Varret M. Rabès J-P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2182) Google Scholar). Mechanistically, PCSK9 binds the epidermal growth factor precursor homology domain A (EGF-A) of the LDL receptor (LDLR) (2Zhang D-W. Lagace T.A. Garuti R. Zhao Z. McDonald M. Horton J.D. Cohen J.C. Hobbs H.H. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.J. Biol. Chem. 2007; 282: 18602-18612Abstract Full Text Full Text PubMed Scopus Google and of the of PCSK9 the of the LDLR in a PubMed Scopus Google the of LDLR to to the and LDL Horton J.D. of low density lipoprotein receptor by proprotein convertase subtilisin/kexin type in Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). relationship between LDL and A of and to to Full Text Full Text PubMed Scopus Google with a of in of PCSK9 Z. Lagace T.A. L. Horton J.D. Cohen J.C. Hobbs H.H. of mutations in PCSK9 and of a Genet. Full Text Full Text PubMed Scopus Google in PCSK9 is and in a 2007; Full Text Full Text PubMed Scopus Google PCSK9 PCSK9 LDL S. D. M. C. R. et of a to PCSK9 on LDL PubMed Scopus Google R. et and of in and cardiovascular PubMed Scopus Google and also cardiovascular et and and in with cardiovascular to such as this a of and a for a for R. et of for cardiovascular in with cardiovascular PubMed Scopus Google K. of PCSK9 on the of the PubMed Scopus Google Scholar). a to PCSK9 function to PCSK9 PubMed Scopus Google Scholar). is a a potentially for of PCSK9 the L. the the proprotein convertase in familial Biol. PubMed Scopus Google D. of proprotein convertase subtilisin/kexin type 9 by binding Full Text Full Text PubMed Scopus Google M. of PCSK9 and by of in Full Text Full Text PubMed Scopus Google R. factor and low density lipoprotein via of the proprotein convertase subtilisin/kexin type 9 Biol. Chem. Full Text Full Text PubMed Scopus Google and M. M. of the proprotein and in PubMed Scopus Google with of PCSK9 itself for its function K. D. et plasma PCSK9 PubMed Scopus Google Scholar). a proprotein PCSK9 between its prodomain and domain to the Benjannet S. Wickham L. S. M. proprotein convertase convertase and 2003; PubMed Scopus Google S. D. R. Wickham L. Varret M. Allard D. et and its and on the low density lipoprotein receptor and LDL Biol. Chem. Full Text Full Text PubMed Scopus Google proprotein convertase subtilisin/kexin type 9 (PCSK9) and Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). PCSK9 not and effect on the LDLR of in in a lipoprotein receptor PubMed Scopus Google Scholar). the which as the of PCSK9 of the PCSK9 its and to Biol. Chem. Full Text Full Text PubMed Scopus Google the prodomain remains but to the domain for the of D. T.A. et and of PCSK9 and its to familial hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google of PCSK9 A homology with the 2007; PubMed Scopus Google S. S. of a regulator of plasma 2007; Full Text Full Text PubMed Scopus Google Scholar). the of PCSK9 on the LDLR and LDL, of PCSK9 M. M. of the proprotein and in PubMed Scopus Google Scholar). this to or of which we not PCSK9 for remains M. S. C. proprotein in hypercholesterolemia and cardiovascular on proprotein convertase subtilisin/kexin PubMed Scopus Google as it for the function of a to cause the for and for PCSK9 the PCSK9 S127R, to that can this S. D. R. Wickham L. Varret M. Allard D. et and its and on the low density lipoprotein receptor and LDL Biol. Chem. Full Text Full Text PubMed Scopus Google C. Horton J.D. Lagace T.A. of secreted PCSK9 increases low density lipoprotein receptor in Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). of that the of LDL, binds PCSK9 and the function of PCSK9 in D. S. L. S. of PCSK9 with its PubMed Scopus Google Z. M. Proprotein convertase subtilisin/kexin type 9 with and its degradation, of the lipoprotein Biol. PubMed Scopus Google M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). the of in Z. M. Proprotein convertase subtilisin/kexin type 9 with and its degradation, of the lipoprotein Biol. PubMed Scopus Google and inhibits the of PCSK9 to LDLR in M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google S. M. J.C. D. et of and low density lipoprotein on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PubMed Scopus Google Scholar). the of PCSK9 in the PCSK9 S. of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) lipoprotein PubMed Scopus Google Scholar). of the remains though the of the PCSK9 prodomain, which is for the PCSK9:LDLR Lagace T.A. Horton J.D. for LDL receptor by PubMed Scopus Google S. R. et of the and on the activity of for Biol. Chem. Full Text Full Text PubMed Scopus Google is required for PCSK9 to LDL M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). heparan sulfate proteoglycans (HSPGs) as coreceptors for PCSK9 on the to PCSK9 uptake and with a in the PCSK9 prodomain as the binding this C. D. S. K. et sulfate proteoglycans PCSK9 to the LDL PubMed Scopus Google Scholar). the of the PCSK9 prodomain in and the for binding we that LDL and heparin-like molecules such as as with to PCSK9 In this study, we a to that PCSK9 uptake We that LDL is a of PCSK9 binding to the LDLR in its to PCSK9 uptake is with inhibitory effect on PCSK9:LDLR we show that inhibition of PCSK9 uptake is on LDLR Additionally, we show that the and the interactions modulate inhibitory effect on PCSK9 uptake. we that the entire PCSK9 prodomain, but not truncated binds LDL in vitro and PCSK9 uptake that HLMs and LDL a PCSK9 binding we show that the of also in the prodomain, increased affinity for a to explain its phenotype. Overall, our findings a model LDL PCSK9 uptake via and a of to modulate in the by L. J.C. of molecules to PubMed Scopus Google of PCSK9 proprotein convertase subtilisin/kexin type 9 (PCSK9) and Biol. Chem. Full Text Full Text PubMed Scopus Google of the PCSK9 its and to Biol. Chem. 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C. et of a that inhibits PCSK9 binding to the low density lipoprotein Biol. Chem. Full Text Full Text PubMed Scopus Google in a of the to also a between PCSK9 and PCSK9 Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. and of plasma PCSK9 PubMed Scopus Google to the of PCSK9 we to via with a PCSK9 not the of this of LDLR on by in Z. of and in PubMed Scopus Google increased for (PCSK9) in for (PCSK9) the of our on the PCSK9:LDLR that our the effect on the LDLR, we cell-surface LDLR via show that of for with cell-surface LDLR in in PCSK9 PCSK9 or PCSK9 PCSK9 We to the inhibitory effect of LDL on between PCSK9 and the domain of the that LDL can the binding of PCSK9 to the LDLR S. M. J.C. D. et of and low density lipoprotein on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PubMed Scopus Google though that this does not a direct between PCSK9 and the LDLR M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). that the a with increased affinity for the domain Lagace T.A. Horton J.D. for LDL receptor by PubMed Scopus Google we a near of PCSK9 and of domain to the D. In of to that the of PCSK9 with the LDL PubMed Scopus Google Scholar). We that and of LDL binding in a we that PCSK9 of of LDL domain binding by Binding Binding of LDL binding by Binding Binding PCSK9 uptake is on the of the LDLR T.A. Garuti R. Horton J.D. PCSK9 decreases the of LDL in and in of PubMed Scopus Google of proprotein convertase subtilisin/kexin type 9 (PCSK9) a via Biol. Chem. Full Text Full Text PubMed Scopus Google and increased by mutations as which the binding affinity of PCSK9 for the LDLR S. M. J.C. D. et of and low density lipoprotein on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PubMed Scopus Google we to our in vitro findings to a We our to the of LDL on PCSK9 uptake. We with in the of low and of In to the of the in vitro LDL PCSK9 uptake with a effect the for Uptake Uptake We our by the with LDL to the to cells. rescued the inhibitory activity of LDL, in more of PCSK9 uptake for Uptake Uptake for Uptake Uptake for Uptake Uptake in PCSK9 uptake for the and though not to the of inhibition in the We this that a factor the of LDL to PCSK9 uptake cells. Furthermore, this factor PCSK9 and LDL to the cells. the by which LDL acts to PCSK9 we PCSK9 uptake LDLR that LDL with PCSK9 for binding to LDLR S. M. J.C. D. et of and low density lipoprotein on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PubMed Scopus Google but PCSK9 uptake can in the of PCSK9:LDLR though the of LDLR itself is required M. 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We the to and the show that the prodomain with LDL the density with for the truncated prodomain the prodomain not to the as LDL in the as by of the in the of LDL for competition of the prodomain for we the prodomain with in the LDL binding to LDL of the in binding of to but show a in binding of which for the prodomain findings to and also the of prodomain we with in our PCSK9 uptake we of with the and LDL to the on PCSK9 uptake. show that of PCSK9 uptake required the prodomain Uptake Uptake suggest a for the entire prodomain, the HSPG binding site, to the LDL to PCSK9 uptake. consistent with the binding for such effect to of PCSK9 as a cause of familial hypercholesterolemia the PCSK9 (1Abifadel M. Varret M. Rabès J-P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2182) Google Scholar). of this and required for PCSK9 to its effect on the LDLR, we and that the is in function and of the PCSK9 its and to Biol. Chem. Full Text Full Text PubMed Scopus Google R. et and of PCSK9 with familial hypercholesterolemia in and Full Text Full Text PubMed Scopus Google Scholar). the of the prodomain and near the HSPG binding we that a this the affinity of PCSK9 for the potentially explaining the phenotype. we the affinity of PCSK9 for in in vitro We S127R, and and the via in cells. We the to a and the of the PCSK9 We the with a by a to the with our the more with or the Furthermore, the the the with We findings to uptake of PCSK9. we our uptake the S127R, and with and cells. show that the in uptake with the for the Uptake Uptake as with Uptake Uptake or PCSK9 Uptake Uptake the of uptake of PCSK9 Uptake Uptake than that of PCSK9 Uptake Uptake consistent with the increased affinity of the for the LDLR domain C. L. S. C. et of a that inhibits PCSK9 binding to the low density lipoprotein Biol. Chem. Full Text Full Text PubMed Scopus Google Scholar). PCSK9 uptake Uptake Uptake than that of PCSK9. of with to effect on LDLR also the in PCSK9 uptake, as by in the of or with of LDL consistent with the affinity for HLMs as with this increased affinity increased uptake and our suggest a LDL a in the of the In this study, we the of LDL as of PCSK9 uptake, a to this of the PCSK9 with we that LDL inhibits PCSK9 uptake in and inhibits binding in vitro M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google S. M. J.C. D. et of and low density lipoprotein on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PubMed Scopus Google Scholar). 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S. et of PCSK9 for Full Text Full Text PubMed Scopus Google Scholar). the of the of the located the HSPG binding of the the of a the binding with HLMs. a a R. et and of PCSK9 with familial hypercholesterolemia in and Full Text Full Text PubMed Scopus Google and a via the of a LDL also inhibits uptake of so in to its on and that the of the is not to with LDL with we on PCSK9 uptake as a to this of the PCSK9 as the of our to that a effect on the uptake of PCSK9 is required for its function on the LDLR, such uptake does not that this function Lagace T.A. PCSK9 recycling LDL in Full Text Full Text PubMed Scopus Google Scholar). our on in vitro and with of our of our remains consistent with that LDL inhibits the of PCSK9 to LDLR degradation, this in and not in M. Lagace T.A. density lipoprotein binds to proprotein convertase subtilisin/kexin (PCSK9) in plasma and inhibits low density lipoprotein receptor degradation.J. Biol. Chem. Full Text Full Text PubMed Scopus Google S. M. J.C. 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