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细胞通过内吞受体 megalin/LRP-2 摄取 proMMP-2:TIMP-2 复合物。

Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2.

机构信息

de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.

Department of Biomedicine, Aarhus University, 8000, Aarhus, Denmark.

出版信息

Sci Rep. 2017 Jun 28;7(1):4328. doi: 10.1038/s41598-017-04648-y.

DOI:10.1038/s41598-017-04648-y
PMID:28659595
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5489529/
Abstract

Matrix metalloproteinases (MMPs) are regulated at multiple transcriptional and post-transcriptional levels, among which receptor-mediated endocytic clearance. We previously showed that low-density lipoprotein receptor-related protein-1 (LRP-1) mediates the clearance of a complex between the zymogen form of MMP-2 (proMMP-2) and tissue inhibitor of metalloproteinases, TIMP-2, in HT1080 human fibrosarcoma cells. Here we show that, in BN16 rat yolk sac cells, proMMP-2:TIMP-2 complex is endocytosed through a distinct LRP member, megalin/LRP-2. Addition of receptor-associated protein (RAP), a natural LRP antagonist, caused accumulation of endogenous proMMP-2 and TIMP-2 in conditioned media. Incubation with RAP also inhibited membrane binding and cellular uptake of exogenous iodinated proMMP-2:TIMP-2. Moreover, antibodies against megalin/LRP-2, but not against LRP-1, inhibited binding of proMMP-2:TIMP-2 to BN16 cell surface. BIAcore analysis confirmed direct interaction between the complex and megalin/LRP-2. Conditional renal invalidation of megalin/LRP-2 in mice resulted in accumulation of proMMP-2 and TIMP-2 in their urine, highlighting the physiological relevance of the binding. We conclude that megalin/LRP-2 can efficiently mediate cell-surface binding and endocytosis of proMMP-2:TIMP-2 complex. Therefore megalin/LRP-2 can be considered as a new actor in regulation of MMP-2 activity, an enzyme crucially involved in many pathological processes.

摘要

基质金属蛋白酶（MMPs）在多个转录和转录后水平受到调节，其中包括受体介导的内吞清除。我们之前表明，低密度脂蛋白受体相关蛋白-1（LRP-1）介导 HT1080 人纤维肉瘤细胞中基质金属蛋白酶-2（proMMP-2）和金属蛋白酶组织抑制剂 TIMP-2 之间酶原形式的复合物的清除。在这里，我们表明，在 BN16 大鼠卵黄囊细胞中，proMMP-2：TIMP-2 复合物通过独特的 LRP 成员巨球蛋白/LRP-2 被内吞。添加受体相关蛋白（RAP），一种天然的 LRP 拮抗剂，导致内源性 proMMP-2 和 TIMP-2 在条件培养基中积累。与 RAP 孵育也抑制外源性碘标记的 proMMP-2：TIMP-2 的膜结合和细胞摄取。此外，针对巨球蛋白/LRP-2 的抗体，但不是针对 LRP-1 的抗体，抑制 proMMP-2：TIMP-2 与 BN16 细胞表面的结合。BIAcore 分析证实了复合物与巨球蛋白/LRP-2 之间的直接相互作用。在小鼠中条件性肾缺失巨球蛋白/LRP-2 导致其尿液中 proMMP-2 和 TIMP-2 的积累，突出了结合的生理相关性。我们得出结论，巨球蛋白/LRP-2 可以有效地介导 proMMP-2：TIMP-2 复合物的细胞表面结合和内吞作用。因此，巨球蛋白/LRP-2 可以被视为调节 MMP-2 活性的新因素，MMP-2 是许多病理过程中至关重要的酶。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/5a01223d85b8/41598_2017_4648_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/783016cf71c7/41598_2017_4648_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/7f5526b82f3c/41598_2017_4648_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/5a01223d85b8/41598_2017_4648_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/783016cf71c7/41598_2017_4648_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/c2360c3b169b/41598_2017_4648_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/fd7600656330/41598_2017_4648_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/7f5526b82f3c/41598_2017_4648_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a167/5489529/5a01223d85b8/41598_2017_4648_Fig5_HTML.jpg

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