Characterization of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Trafficking Reveals a Novel Lysosomal Targeting Mechanism via Amyloid Precursor-like Protein 2 (APLP2)

DeVay, Rachel M.; Shelton, David L.; Hong, Lei

doi:10.1074/jbc.m113.453373

Cited by 57 publications

(80 citation statements)

References 44 publications

(68 reference statements)

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“…Once released from the cell surface, sortilin does not influence PCSK9 activity 37) . Recently, two proteins were suggested to enhance PCSK9-mediated degradation of the LDL receptor: one is sortilin, which binds to PCSK9 in the trans-Golgi network and possibly facilitates its secretion 37) , and the other is amyloid precursor-like protein 2 (APLP2), which facilitates trafficking of the PCSK9-LDL receptor complex to endosomes/lysosomes 38) . However, Butkinaree et al 39) reported that PCSK9 enhanced LDL receptor degradation independent of sortilin or APLP2 ex vivo The present study has several limitations.…”

Section: Discussionmentioning

confidence: 99%

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue

Hashimoto

Ogawa

et al. 2016

JAT

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Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein (LDL) cholesterol levels, and sortilin is linked to lipoprotein metabolism. Although statin therapy increases PCSK9 levels, effects of this therapy on plasma sortilin levels have not been evaluated. The purpose of the present study was to examine the effects of statins on plasma PCSK9 and sortilin levels, and association of statin-induced increase in PCSK9 levels with sortilin. Methods: Serum lipid levels and plasma PCSK9 and sortilin levels were measured at baseline and 8 months after statin therapy in 90 statin-naive patients with coronary artery disease (CAD). Pitavastatin 4 mg/day was used to treat 44 patients and pravastatin 20 mg/day to treat the remaining 46 patients. Results: For both statin groups, significant increases in hetero-dimer PCSK9 levels (pitavastatin: 31%, p 0.0001; pravastatin: 34%, p 0.03) and decreases in sortilin levels (pitavastatin: 8%, p 0.02; pravastatin: 16%, p 0.002) were observed. Although a reduction in LDL cholesterol was greater in the pitavastatin group than in the pravastatin group, no significant differences were observed in percentage changes in hetero-dimer PCSK9 and sortilin levels. A significant positive correlation was observed between percentage changes in hetero-dimer PCSK9 levels and those in sortilin levels (pitavastatin: r 0.359, p 0.02; pravastatin: r 0.276, p 0.06). Conclusions: Use of pitavastatin and pravastatin increased plasma PCSK9 and decreased sortilin levels. Statin-induced increases in PCSK9 were associated with changes in sortilin in statin-naive patients with CAD. J Atheroscler Thromb, 2016; 23: 848-856.

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Section: Discussionmentioning

confidence: 99%

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue

Hashimoto

Ogawa

et al. 2016

JAT

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“…17 Nevertheless, because the cytosolic tail of the LDLR is not necessary for the sorting of the [PCSK9≡LDLR] complex to lysosomes, 44,55 this suggests that another protein must bind the luminal CHRD domain and that such protein X would also have a transmembrane domain and cytosolic tail linking motor proteins in the cytosol to direct the complex to lysosomes (Figure 1). 44 In that context, a recent report proposed that the amyloid precursor-like protein-2 (APLP-2) can bind the CHRD at the surface of cells and in endosomes, and that this [LDLR≡PCSK9≡APLP-2] tripartite complex is then targeted to lysosomes (Figure 2), 56 by a still undefined mechanism.…”

mentioning

confidence: 99%

Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

502

197

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“…PCSK9 was found to bind through its C-terminal domain to APLP2 at acidic pH, followed by transport to the lysosome. This CL pathway did not require binding of PCSK9 to the LDLR ( 34 ). However, when PCSK9 was bound to LDLR via its catalytic domain, it formed a bridge to APLP2, which facilitated LDLR transport to the lysosome.…”

Section: Proteolytic Cleavage Of Pcsk9 Slows the CL Of Ly From Serummentioning

confidence: 94%

“…We can propose a mechanism which links PCSK9 accumulation to the more rapid CL of the antibodies based on the studies in DeVay and coworkers ( 34,35 ). These authors demonstrated that an anti-PCSK9 antibody was delivered to lysosomes for degradation by a specifi c pathway involved in PCSK9 CL.…”

Section: Proteolytic Cleavage Of Pcsk9 Slows the CL Of Ly From Serummentioning

confidence: 99%

“…These authors demonstrated that an anti-PCSK9 antibody was delivered to lysosomes for degradation by a specifi c pathway involved in PCSK9 CL. Although the LDLR is involved in the CL of PCSK9 ( 14 ), it is not the primary mediator of this pathway, as the antibody prevents the binding of PCSK9 to the LDLR ( 34 ). The key mediator of the pathway was amyloid precursor protein 2 (APLP2), a transmembrane protein that binds major histocompatibility complex class I molecules and targets them to lysosomes ( 36 ).…”

Section: Proteolytic Cleavage Of Pcsk9 Slows the CL Of Ly From Serummentioning

confidence: 99%

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Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

Schroeder

Beyer

Hansen

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org atherosclerosis ( 7,8 ). Conversely, loss-of-function mutations are associated with reduced LDL-C and reduced risk of cardiovascular diseases ( 9-11 ).PCSK9 is expressed in multiple tissues, including liver, intestine, kidney, and cerebellum, of which the liver appears to be the major source of the circulating protein (12)(13)(14). It is synthesized as a 74 kDa proprotein, which is activated prior to secretion by the autocatalytic cleavage of its N-terminal prodomain ( 15 ). PCSK9 that is secreted from cells is comprised of the 14 kDa prodomain associated noncovalently with a 60 kDa mature domain, the latter consisting of an N-terminal catalytic domain and a cysteine-and histidine-rich C-terminal domain. In addition to this 74 kDa form (intact PCSK9), a smaller form (truncated PCSK9) is found in serum in which the N terminus of the catalytic domain is truncated by 7-8 kDa. This truncated PCSK9 represents up to 40% of the total circulating PCSK9 in humans (16)(17)(18). The site of cleavage in PCSK9 was identifi ed as Arg218 of the catalytic domain ( 16,17 ). Furin appears to be responsible for most of the cleavage in vivo, based on studies in mice with hepatocytespecifi c inactivation of the protease ( 18 ). The observation of reduced plasma levels of the truncated PCSK9 in humans heterozygous for the R218S gain-of-function mutation is also consistent with furin-mediated cleavage, as this mutation disrupts the RXXR sequence recognized by furin ( 18 ).Several reports have addressed the question of whether the truncated PCSK9 is active in the regulation of LDL-C. Studies in furin knockout mice found reduced circulating levels of truncated PCSK9 and less hepatic LDLR than in Abstract Lilly PCSK9 antibody LY3015014 (LY) is a monoclonal antibody (mAb) that neutralizes proprotein convertase subtilisin-kexin type 9 (PCSK9). LY decreases LDL cholesterol in monkeys and, unlike other PCSK9 mAbs, does not cause an accumulation of intact PCSK9 in serum. Comparing the epitope of LY with other clinically tested PCSK9 mAbs, it was noted that the LY epitope excludes the furin cleavage site in PCSK9, whereas other mAbs span this site. In vitro exposure of PCSK9 to furin resulted in degradation of PCSK9 bound to LY, whereas cleavage was blocked by other mAbs. These other mAbs caused a signifi cant accumulation of serum PCSK9 and displayed a shorter duration of LDL-cholesterol lowering than LY when administered to mice expressing the WT human PCSK9. In mice expressing a noncleavable variant of human PCSK9, LY behaved like a cleavage-blocking mAb, in that it caused signifi cant PCSK9 accumulation, its duration of LDL lowering was reduced, and its clearance (CL) from serum was accelerated. Thus, LY neutralizes PCSK9 and allows its proteolytic degradation to proceed, which limits PCSK9 accumulation, reduces the CL rate of LY, and extends its duration of action.PCSK9 mAbs with this property are likely to achieve longer durability and require lower doses than mAbs that cause antigen...

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Characterization of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Trafficking Reveals a Novel Lysosomal Targeting Mechanism via Amyloid Precursor-like Protein 2 (APLP2)

Cited by 57 publications

References 44 publications

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Pcsk9

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

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