Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1).
Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1).
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DOI：
10.1371/journal.pone.0064145
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Seidah NG
中科院分区：
文献类型：
--
作者：
Canuel M;Sun X;Asselin MC;Paramithiotis E;Prat A;Seidah NG
LDL-胆固醇（LDLc）水平升高是心血管疾病和动脉粥样硬化的主要危险因素。LDL c通过LDL受体（LDLR）从循环中清除。前蛋白转化酶枯草杆菌蛋白酶/kexin 9（PCSK 9）可增强内体/溶酶体中LDLR的降解，导致循环LDLc升高。PCSK 9还可介导缺乏胞质尾的LDLR降解，表明存在尚未确定的溶酶体靶向因子。在此，我们证实了这一点，也消除了LDLR的跨膜结构域在介导其PCSK 9诱导的内化和降解中的作用。我们实验室的最新发现也表明PCSK 9在增强肿瘤转移中的作用。我们在此表明，虽然LDLR对小鼠B16 F1黑色素瘤细胞中的PCSK 9不敏感，但PCSK 9能够诱导低密度脂蛋白受体相关蛋白1（LRP-1）的降解，表明这些受体的不同靶向机制。此外，PCSK 9仍然能够作用于缺乏LRP-1的CHO 13-5-1细胞中的LDLR。相反，在CHO-A7细胞中，在不存在LDLR的情况下，PCSK 9也作用于LRP-1，其中LDLR的重新引入导致PCSK 9介导的LRP-1降解减少。因此，虽然PCSK 9能够诱导LRP-1的降解，但后者不是LDLR调节的必需因子，但LDLR有效地与LRP-1竞争PCSK 9活性。PCSK 9靶点的鉴定应有助于更好地了解PCSK 9抑制对降低LDLc和肿瘤转移的影响。
Elevated LDL-cholesterol (LDLc) levels are a major risk factor for cardiovascular disease and atherosclerosis. LDLc is cleared from circulation by the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDLc. PCSK9 can also mediate the degradation of LDLR lacking its cytosolic tail, suggesting the presence of as yet undefined lysosomal-targeting factor(s). Herein, we confirm this, and also eliminate a role for the transmembrane-domain of the LDLR in mediating its PCSK9-induced internalization and degradation. Recent findings from our laboratory also suggest a role for PCSK9 in enhancing tumor metastasis. We show herein that while the LDLR is insensitive to PCSK9 in murine B16F1 melanoma cells, PCSK9 is able to induce degradation of the low density lipoprotein receptor-related protein 1 (LRP-1), suggesting distinct targeting mechanisms for these receptors. Furthermore, PCSK9 is still capable of acting upon the LDLR in CHO 13-5-1 cells lacking LRP-1. Conversely, PCSK9 also acts on LRP-1 in the absence of the LDLR in CHO-A7 cells, where re-introduction of the LDLR leads to reduced PCSK9-mediated degradation of LRP-1. Thus, while PCSK9 is capable of inducing degradation of LRP-1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP-1 for PCSK9 activity. Identification of PCSK9 targets should allow a better understanding of the consequences of PCSK9 inhibition for lowering LDLc and tumor metastasis.
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影响因子：
8
作者：
Kysenius, Kai;Muggalla, Pranuthi;Huttunen, Henri J.
通讯作者：
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影响因子：
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Mayer, Gaetan;Poirier, Steve;Seidah, Nabil G.
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Dedieu, S.
影响因子：
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作者：
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通讯作者：
Boucher, Philippe