Sec22b determines Weibel-Palade body length by controlling anterograde ER-Golgi transport.
Sec22b determines Weibel-Palade body length by controlling anterograde ER-Golgi transport.
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DOI：
10.3324/haematol.2019.242727
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发表时间：
2021-04-01
期刊：
影响因子：
10.1
通讯作者：
Bierings R
中科院分区：
文献类型：
--
作者：
Karampini E;Bürgisser PE;Olins J;Mulder AA;Jost CR;Geerts D;Voorberg J;Bierings R
血管性血友病因子（VWF）是一种多聚体止血蛋白，在内皮细胞中合成，储存在称为韦伯-帕拉德体（WPB）的细长分泌细胞器中分泌。VWF的止血活性与这些小体的长度密切相关，但内皮细胞如何控制其WPB的尺寸尚不清楚。在这项研究中，使用靶向短发夹RNA筛选，我们确定longin-SNARE Sec 22 b作为WPB大小和VWF运输的新决定因素。我们发现Sec 22 b缺失导致典型的细长WPB形态的丧失以及高尔基体的解体和粗面内质网池的扩张。这是伴随着减少蛋白水解加工的VWF，积累的VWF在扩张的粗面内质网和减少的基础和刺激的VWF分泌。我们的数据表明，WPB的伸长，从而其货物VWF的粘附活性，是由内质网和高尔基体之间的顺行运输的速率，这取决于Sec 22 b含有SNARE复合物。
Von Willebrand factor (VWF) is a multimeric hemostatic protein that is synthesized in endothelial cells, where it is stored for secretion in elongated secretory organelles called Weibel-Palade bodies (WPB). The hemostatic activity of VWF is strongly related to the length of these bodies, but how endothelial cells control the dimensions of their WPB is unclear. In this study, using a targeted short hairpin RNA screen, we identified longin-SNARE Sec22b as a novel determinant of WPB size and VWF trafficking. We found that Sec22b depletion resulted in loss of the typically elongated WPB morphology together with disintegration of the Golgi and dilation of rough endoplasmic reticulum cisternae. This was accompanied by reduced proteolytic processing of VWF, accumulation of VWF in the dilated rough endoplasmic reticulum and reduced basal and stimulated VWF secretion. Our data demonstrate that the elongation of WPB, and thus adhesive activity of their cargo VWF, is determined by the rate of anterograde transport between endoplasmic reticulum and Golgi, which depends on Sec22b-containing SNARE complexes.