Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-β1.
Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-β1.
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DOI：
10.1371/journal.pone.0033163
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Granville DJ
中科院分区：
文献类型：
--
作者：
Boivin WA;Shackleford M;Vanden Hoek A;Zhao H;Hackett TL;Knight DA;Granville DJ
颗粒酶B （GrB）是一种促凋亡丝氨酸蛋白酶，有助于免疫介导的靶细胞凋亡。然而，在炎症期间，GrB在细胞外空间积聚，保持其活性，并能够切割细胞外基质（ECM）蛋白。最近的研究表明GrB在心血管疾病中具有致病性的细胞外作用，但细胞外GrB活性的病理生理后果在很大程度上仍然未知。本研究的目的是鉴定GrB的蛋白多糖（PG）底物，并检测GrB将PG隔离的TGF-β1释放到细胞外环境的能力。鉴定了三种细胞外GrB PG底物；Decorin， biglycan和betaglycan。由于所有这些PG都能隔离活性TGF-β1，因此我们进行了细胞因子释放试验，以确定grb介导的PG切割是否能诱导TGF-β1释放。我们的数据证实，GrB从所有三种底物以及内源性ECM中释放TGF-β1，并且该过程被GrB抑制剂3,4-二氯异香豆素抑制。释放的TGF-β1通过诱导人冠状动脉平滑肌细胞SMAD-3磷酸化而保持活性。除了促进体内ECM降解和组织结构完整性的丧失外，细胞外GrB活性的增加还能够诱导pg释放活性TGF-β1。
Granzyme B (GrB) is a pro-apoptotic serine protease that contributes to immune-mediated target cell apoptosis. However, during inflammation, GrB accumulates in the extracellular space, retains its activity, and is capable of cleaving extracellular matrix (ECM) proteins. Recent studies have implicated a pathogenic extracellular role for GrB in cardiovascular disease, yet the pathophysiological consequences of extracellular GrB activity remain largely unknown. The objective of this study was to identify proteoglycan (PG) substrates of GrB and examine the ability of GrB to release PG-sequestered TGF-β1 into the extracellular milieu. Three extracellular GrB PG substrates were identified; decorin, biglycan and betaglycan. As all of these PGs sequester active TGF-β1, cytokine release assays were conducted to establish if GrB-mediated PG cleavage induced TGF-β1 release. Our data confirmed that GrB liberated TGF-β1 from all three substrates as well as from endogenous ECM and this process was inhibited by the GrB inhibitor 3,4-dichloroisocoumarin. The released TGF-β1 retained its activity as indicated by the induction of SMAD-3 phosphorylation in human coronary artery smooth muscle cells. In addition to contributing to ECM degradation and the loss of tissue structural integrity in vivo, increased extracellular GrB activity is also capable of inducing the release of active TGF-β1 from PGs.
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影响因子：
16
作者：
Afonina IS;Tynan GA;Logue SE;Cullen SP;Bots M;Lüthi AU;Reeves EP;McElvaney NG;Medema JP;Lavelle EC;Martin SJ
通讯作者：
Martin SJ
影响因子：
2.4
作者：
Bae, Y. -A.;Kim, S. -H.;Kong, Y.
通讯作者：
Kong, Y.
影响因子：
4.8
作者：
Harris, JL;Peterson, EP;Craik, CS
通讯作者：
Craik, CS
影响因子：
5.4
作者：
ISAAZ, S;BAETZ, K;GRIFFITHS, GM
通讯作者：
GRIFFITHS, GM
DOI：
10.1161/01.atv.0000147162.51930.b7
发表时间：
2004-12-01
影响因子：
8.7
作者：
Choy, JC;Hung, VHY;Granville, DJ
通讯作者：
Granville, DJ