Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease.
Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease.
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DOI：
10.1038/srep41871
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发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Apte SS
中科院分区：
文献类型：
--
作者：
Hubmacher D;Schneider M;Berardinelli SJ;Takeuchi H;Willard B;Reinhardt DP;Haltiwanger RS;Apte SS
分泌的金属蛋白酶在细胞外基质的形成、重塑和破坏中具有多种作用。分泌金属蛋白酶ADAMTS17的隐性突变导致weil - marchesani样综合征患者的晶状体异位和矮小，以及狗的原发性开角型青光眼和晶状体异位。人们对这种蛋白酶及其与纤维蛋白微原纤维的联系知之甚少，纤维蛋白微原纤维的主要成分纤维蛋白-1在遗传上与异位晶状体和身高改变有关。纤维蛋白微原纤维形成眼带，存在于眼睛的引流装置中。我们发现重组ADAMTS17具有独特的特征和不同寻常的生命周期。它从细胞中分泌出来后，在反式中进行快速的自催化处理。ADAMTS17的分泌需要O-聚焦，其自催化活性不依赖于furin对前肽的加工。ADAMTS17与重组纤维蛋白-2结合，但不与纤维蛋白-1结合，也不裂解。它在培养成纤维细胞中与含有纤维蛋白1的微原纤维共定位，并抑制纤维蛋白2 （FBN2）在微原纤维中的结合，部分原因是FBN2 mRNA表达的转录下调。RNA原位杂交检测到Adamts17在眼睛、骨骼和其他器官的特定结构中表达，它可能调节微原纤维的原纤维异构体组成。
Secreted metalloproteases have diverse roles in the formation, remodeling, and the destruction of extracellular matrix. Recessive mutations in the secreted metalloprotease ADAMTS17 cause ectopia lentis and short stature in humans with Weill-Marchesani-like syndrome and primary open angle glaucoma and ectopia lentis in dogs. Little is known about this protease or its connection to fibrillin microfibrils, whose major component, fibrillin-1, is genetically associated with ectopia lentis and alterations in height. Fibrillin microfibrils form the ocular zonule and are present in the drainage apparatus of the eye. We show that recombinant ADAMTS17 has unique characteristics and an unusual life cycle. It undergoes rapid autocatalytic processing in trans after its secretion from cells. Secretion of ADAMTS17 requires O-fucosylation and its autocatalytic activity does not depend on propeptide processing by furin. ADAMTS17 binds recombinant fibrillin-2 but not fibrillin-1 and does not cleave either. It colocalizes to fibrillin-1 containing microfibrils in cultured fibroblasts and suppresses fibrillin-2 (FBN2) incorporation in microfibrils, in part by transcriptional downregulation of Fbn2 mRNA expression. RNA in situ hybridization detected Adamts17 expression in specific structures in the eye, skeleton and other organs, where it may regulate the fibrillin isoform composition of microfibrils.