The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis

Bierings, Ruben; Hellen, Nicola; Kiskin, Nikolai I.; Knipe, Laura; Fonseca, Ana Violeta; Patel, Bijal; Meli, A.; Rose, Marlene L.; Hannah, Matthew J.; Carter, Tom

doi:10.1182/blood-2012-05-429936

Cited by 87 publications

(181 citation statements)

References 50 publications

(84 reference statements)

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“…Among these, the implication of a series of intracellular proteins (including but not limited to: RalA, Rab3, Rab27a, Rab15, Rab33a, Rab37, Munc13-4, Munc18c, Slp4a, Annexin A2-S100A10, syntaxin-binding protein 1, syntaxin-4, VAMP-3, G proteins) has been documented based on the finding that deletion or mutation of these proteins modulates constitutive and/or regulated release of VWF. 44,[65][66][67][68][69][70][71][72][73] Recently, an unexpected and novel type of regulation of VWF release has been reported by Torisu and colleagues. 74 Not only did they observe that WPBs are often in close proximity of autophagosomes but they also detected the presence of VWF in these organelles.…”

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

318

333

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To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...

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Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

318

333

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“…29 WPBs contain a cocktail of (Rab3 A, B, and D). 22,23,25,29 Slp4-a is reported to bind to these secretory Rabs via its N-terminal SHD.…”

Section: N-terminal Shd Mediates Wpb Localization But Is Not Sufficiementioning

confidence: 99%

“…29 WPBs contain a cocktail of (Rab3 A, B, and D). 22,23,25,29 Slp4-a is reported to bind to these secretory Rabs via its N-terminal SHD. 37 We speculated that this region was responsible for recruitment of Slp4-a to WPBs and for this purpose we expressed epitope-tagged fusion proteins of Slp4-a truncations that consist of, or lack, the SHD ( Figure 1A).…”

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confidence: 99%

STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a

Breevoort

Snijders

Hellen

et al. 2014

Blood

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Key Points• Recruitment of STXBP1 by Slp4-a promotes WeibelPalade body exocytosis.• Ex vivo EIEE4 endothelial cells haploinsufficient for STXBP1 have impaired Weibel-Palade body exocytosis.Vascular endothelial cells contain unique rod-shaped secretory organelles, called WeibelPalade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormoneevoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine-and forskolin-induced VWF secretion.To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploinsufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine-and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4-a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature. (Blood. 2014;123(20):3185-3194) IntroductionEndothelial cells line the lumen of all blood vessels, providing a highly dynamic barrier that plays a crucial role in maintaining vascular homeostasis. They contain specialized secretory organelles called Weibel-Palade bodies (WPBs) that allow the endothelium to store and release, in a regulated fashion, a presynthesized cocktail of hemostatic, inflammatory, and angiogenic mediators in response to endothelial activation, injury, or stress. [1][2][3] The main component of these organelles is von Willebrand factor (VWF), a multimeric glycoprotein crucial for platelet plug formation and stabilizing coagulation factor VIII. In addition to VWF, several soluble chemokines (eg,, IL-8) as well as the integral membrane proteins CD63 and P-selectin are stored in these organelles. [4][5][6][7][8][9] Coordinated expression of CD63 and P-selectin on the endothelial cell surface after WPB exocytosis is crucial for leukocyte extravasation at sites of inflammation. 10 The presence of angiopoietin-2 and insulin-like growth factor-binding protein 7 in WPBs points toward a critical role for the organelle in regulation of angiogenesis. 11-13The precise composition of mediators stored in WPBs depends crucially on the physical, mechanical, and chemical signals in the local microenvironment; for example, targeting of eotaxin-3, IL-8, and IL-6 has been observed in response to pro-...

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“…Recent studies have defined some of the endothelial proteins that control vesicle secretory pathway in ECs. Syntaxins, vesicle-associated membrane proteins (VAMPs), synaptosomalassociated proteins (SNAPs), NSF, α-synuclein, and various small GTPases and their effectors (such as Rab11, RalA, Rap1, Rab27a, MyRIP, and Slp4-a) play a critical role in endothelial granule exocytosis (27)(28)(29)(30)(31)(32)(33)(34); NO and thioredoxin regulate exocytosis by chemically modifying NSF (35,36); and an assortment of secretagogues or pathologic stimuli can stimulate granule secretion from human…”

Section: Introductionmentioning

confidence: 99%

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

et al. 2014

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The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis

Cited by 87 publications

References 50 publications

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

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