Weibel-Palade bodies recruit Rab27 by a content-driven, maturation-dependent mechanism that is independent of cell type. 8600 Rockville Pike Exocytosis of Weibel-Palade bodies: how to unpack a vascular emergency kit. Li P., Wei G., Cao Y., Deng Q., Han X., Huang X., et al. Similarly, overexpression of Rab3D or constitutively active Rab3D (Q81L) inhibits agonist-induced secretion and causes the formation of large spherical WPBs. doi: 10.1002/pul2.12146. 2021 Dec 16;9:813995. doi: 10.3389/fcell.2021.813995. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. High-pressure freezing provides insights into Weibel-Palade body biogenesis. In the endoplasmic reticulum (ER), pro-VWF assembles into dimers (also called protomers) in a tail-to-tail fashion by forming interchain disulfide bonds between CK domains.18, After arrival in the trans-Golgi network (TGN), dimers of pro-VWF assemble into multimers by forming head-to-head interchain disulfide bonds between D3 domains and subsequently the propeptide is cleaved, probably by furin.18,19 Multimerization depends on the decrease in pH between the ER (pH 7.2) and TGN (pH 6.2)20 and is blocked by treatment of cells with a weak base.21. Following recruitment of cargo at the TGN, there is a second wave of recruitment that delivers integral and peripheral membrane proteins to WPBs, some of which is AP3 dependent. Endothelial Exocytosis of Angiopoietin-2 Resulting from CCM3 Deficiency Contributes to Cerebral Cavernous Malformation. Please confirm you are a human by completing the captcha challenge below. Dynein-dynactin complex mediates protein kinase A-dependent clustering of Weibel-Palade bodies in endothelial cells. They carry a variety of bioactive molecules that are needed to mount a rapid response to the complex environment of cells that lin Formation and function of Weibel-Palade bodies These bodies function to store two principal molecules, P-selectin and Von Willebrand factor. As such they seal blood vessels and control traffic of nutrients, hormones, growth and differentiation factors, particles and cells (immune cells, metastasizing tumor cells and even pathogens) to and from the vasculature. Clathrin-coated profiles on the secretory pods suggest remodeling via a clathrin-mediated pathway. Mutations C1157F and C1234W of von Willebrand factor cause intracellular retention with defective multimerization and secretion. Scale bars represent 100 nm. A defined clathrin-mediated trafficking pathway regulates sFLT1/VEGFR1 secretion from endothelial cells. Pathways followed by microperoxidase across the endothelium. A.V., and J.V. use of Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells. Impact, diagnosis and treatment of von Willebrand disease. Domains D1D2 (741 aa, 100 kDa) represent the propeptide, and the other domains ranging from domain D to the cysteine knot (CK) domain (2050 aa, 260 kDa) represent mature VWF. However, our picture of the organelle is far from complete and important questions, e.g. Both the D1 and D2 domains have a conserved CGLC motif that resembles the active sites of protein disulfide isomerases, and these motifs are required for VWF multimerization. Authors Johannes Na 1 , Julian Terglane 1 , Volker Gerke 1 Affiliation Simultaneously, Ral-dependent activation of phospholipase D1 induces accumulation of fusogenic lipids (5) that facilitate fusion of WPBs after the Munc18c-assisted assembly of the SNARE-complex (6). Here, another Rab27a effector, the mammalian uncoordinated 134 (Munc13-4), has been shown to promote WPB exocytosis most likely by providing a link or tether between the organelle surface and a PM-bound complex consisting of annexin A2 (AnxA2) and S100A10 (Zografou et al., 2012; Chehab et al., 2017) (Figure 1). Pulm Circ. [Formation and function of Weibel-Palade bodies] - PubMed Elongated WPB morphology is correlated to longer VWF strings with better adhesive properties. Blood. WPB formation is driven by VWF that is produced at the ER and trafficked to the Golgi (1). They could support exocytotic membrane fusion and VWF expulsion but potentially could also prevent fused WPB from fully collapsing into the PM, for example to permit rapid and spatially restricted compensatory endocytosis that has been shown to occur on the membrane of fused WPB (Stevenson et al., 2017). Views Share Tools Weibel-Palade bodies (WPBs) are secretory organelles used for post-synthesis storage in endothelial cells that can, very rapidly, be triggered to release their contents. VWF tubules can extend the entire length of a WPB but are sometimes truncated (Figure 2).3,47,48 Tubules within immature WPBs tend to be curved and disorganized, but in mature WPBs the tubules usually are regularly arranged, with a majority running parallel from end to end of the WPB.3,23,47 Tomographic reconstructions of entire WPBs indicate that VWF tubules gently twist inside the mature WPB, which could mean that tubules are spring-loaded. On the other hand, post-Golgi maturation is accompanied by acquisition of additional cytosolic and also endosomal/lysosomal components. Unauthorized use of these marks is strictly prohibited. Furthermore, it was shown that these structures, in an active myosin motor-dependent process, are required for the efficient release of highly multimeric VWF cargo from the fused WPB (Nightingale et al., 2011). Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells. Basal secretion, typically of less multimeric VWF, provides the circulation with low levels of these VWF species, and constitutive secretion, preferentially occurring at the basolateral membrane surface of endothelial cells, deposits VWF in the subendothelial matrix. Weibel-Palade bodies (WPBs) are the storage granules of endothelial cells, the cells that form the inner lining of the blood vessels and heart. J Cell Biol. These bodies function to store two principal molecules, P-selectin and Von Willebrand factor. Endothelial cells can exhibit different modes of exocytosis. It follows that the rounding up of WPBs and particularly of large secretory pods could lead to the bulging of endothelial cells that might constrict blood flow or cause turbulence, especially in the microvasculature. National Library of Medicine The endothelium can quickly deliver bioactive molecules by regulated exocytosis of its secretory granules, the Weibel-Palade bodies (WPBs). 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. The arrows indicate 4 distinct noncovalent domain-domain interactions. eCollection 2021. Frontiers | HPS6 Regulates the Biogenesis of Weibel-Palade Body in They are found in arteries, capillaries, veins, and the endocardium, but notably not in the lymphatic vessels. Here, we review what is currently known about their formation. (2016). Miklavc P., Ehinger K., Sultan A., Felder T., Paul P., Gottschalk K.-E., et al. Thrombin up-regulates the Angiopoietin/Tie2 axis: EPCR occupancy prevents the thrombin mobilization of angiopoietin2 and P-selectin from Weibel-Palade bodies. A GBF1-dependent Mechanism for Environmentally Responsive Regulation of ER-Golgi Transport. (A) The orderly twisting of the tubules within WPBs is illustrated by the surface rendered tubules on a tomographic slice. Before Scale bar, 1 m. Ma J., Zhang Z., Yang L., Kriston-Vizi J., Cutler D. F., Li W. (2016). MC_UU_00012/2/MRC_/Medical Research Council/United Kingdom, MC_UU_12018/2/MRC_/Medical Research Council/United Kingdom, PG/14/76/31087/BHF_/British Heart Foundation/United Kingdom. Thus, WPB are pivotal components of the precisely tuned machinery that orchestrates blood vessel homeostasis. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. The AP-1 effectors aftiphilin and -synergin are recruited to forming WPBs and exhibit partial colocalization with immature perinuclear WPBs. Targeting to the WPB requires the VWF propeptide.17 VWF tubules have only been identified in the TGN and not in other cisternae of the Golgi, suggesting that they form at this stage.23 WPB formation can be prevented by overexpression of a dominant-negative AP180 construct that blocks clathrin coat formation or by siRNA knockdown of AP-1. Whereas earlier studies had identified the Ca2+/phospholipid-binding protein annexin A8 as a LEL-localized component of the machinery facilitating LEL-to-WPB delivery of CD63 (Poeter et al., 2014), Sharda and coworkers (Sharda et al., 2020) recently reported the participation of biogenesis of lysosome related organelle-2 (BLOC-2), a protein that can be mutated in the recessive bleeding disorder Hermansky-Pudlak syndrome. (2017). Morphology of WPBs in nonstimulated cells. (A) Conventional exocytosis in which single WPBs fuse with the plasma membrane, thereby releasing their cargo. Composition of the von Willebrand factor storage organelle (Weibel-Palade body) isolated from cultured human umbilical vein endothelial cells. Synaptotagmin 5 Regulates Calcium-dependent Weibel-Palade Body Exocytosis in Human Endothelial Cells. Importantly, a mutant synaptotagmin-5 lacking the Ca2+ coordinating asparagine residue in the C2A domain negatively interferes with histamine evoked WPB exocytosis directly showing the importance of synaptotagmin-5 Ca2+ binding (Lenzi et al., 2019). Type 2N von Willebrand disease due to compound heterozygosity for R854Q and a novel R763G mutation at the cleavage site of von Willebrand factor propeptide. (2019). Fusion between WPBs and other organelles could modify the pH, but fusion between WPBs and lysosomes or endosomes is unlikely because secretory pods lack the endosome/lysosome marker, lysosomal-associated membrane protein 1. Nightingale T. D., White I. J., Doyle E. L., Turmaine M., Harrison-Lavoie K. J., Webb K. F., et al. The site is secure. PDF ADAMTS13: A New Link Between Thrombosis and Inflammation Epub 2002 Jan 19. (2016). Weibel Palade Bodies Article - StatPearls (B) Scanning EM of VWF strings at the surface of stimulated HUVECs displaying numerous branching VWF strings. Changes with WPB maturation include a striking increase in electron density and a corresponding decrease in the separation between the electron dense tubules. HHS Vulnerability Disclosure, Help The DD3 domain in the center is flanked by 2 D1D2 domains (because the orientation of the propeptide is not yet known, a and b represent either D1 or D2). Shopping cart Differential recruitment of cargo proteins to WPBs, slow recruitment of membrane proteins during WPB maturation, and tissue-specific differences in endothelial cell phenotype lead to a heterogeneous population of WPBs.2,40 These processes contribute to the emerging concept of WPB plasticity, which can enable specialized secretory responses depending on the applied stimulus, recent history and location of the cell.10. The site is secure. Watanabe A., Hataida H., Inoue N., Kamon K., Baba K., Sasaki K., et al. In this configuration the AnxA2/S100A10 complex most likely functions as a module binding Ca2+-dependently to PM phospholipids [e.g. Thus, a complex interplay of Ca2+-regulated proteins, also including the recently identified Slp2-a (Francis et al., 2021), likely transmits the rise in intracellular Ca2+ to WPB-PM docking and fusion in the course of regulated exocytosis. designed figures; and all authors contributed to the writing of the paper. (B) Reconstruction of VWF tubules assembled in vitro at pH 6.2 from purified dimeric DD3 and D1D2 domains. PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. An official website of the United States government. As the Rab46 negative, P-selectin containing WPB exocytose under these conditions, only a fraction of the WPB cargo, e.g. Blood Adv. Inclusion in an NLM database does not imply endorsement of, or agreement with, This review will discuss aspects of WPB biogenesis, trafficking and exocytosis focussing on recent findings describing factors contributing to WPB maturation, WPB-actin interactions and WPB-plasma membrane tethering and fusion. 2018 Jul;38(7):1549-1561. doi: 10.1161/ATVBAHA.117.310701. On exocytosis, the propeptide, which is not covalently bound to VWF in WBPs, is rapidly released,82 whereas secreted VWF multimers form strings that can remain associated with cells for a considerable time.48,49 VWF string formation is triggered by the neutral extracellular pH and is impaired if the pH within the WPBs is increased by pretreatment with monensin, which also causes the disappearance of VWF tubules and the rounding up of WPBs. Correspondence: Dr J. Eikenboom, Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; e-mail: h.c.j.eikenboom@lumc.nl. A special enrichment of certain PM phospholipids is indeed observed at WPB-PM fusion sites and inhibitor and depletion experiments suggest that PI(4,5)P2 and the PI(4,5)P2 producing PI4P 5-kinase are required for efficient histamine-evoked WPB exocytosis (Nguyen et al., 2020). However, a more complex mutation at the furin cleavage site, deletion 2269_2270delCT, results in alternative splicing across intron 17 and causes persistence of pro-VWF.12,62 When expressed in AtT-20 cells, this variant is targeted to storage granules, in contrast to the R763G mutation, indicating that the persistence of pro-VWF per se does not prevent granular storage. WPBs include proteins that initiate both haemostasis and inflammation, as well those that modulate blood pressure and angiogenesis. Rojo Pulido I., Nightingale T. D., Darchen F., Seabra M. C., Cutler D. F., Gerke V. (2011). The remarkable architecture of WPBs is because of the unique properties of their major constituent VWF. Residue 416 is Arg in the canine D2 domain and Gln in the human, and the mutation R416Q enables the canine propeptide to support both multimerization and storage in WPBs of human mature VWF. Only later these peculiar membrane compartments were shown to contain the major platelet adhesion molecule von-Willebrand factor (VWF) and the leukocyte receptor P-selectin (Wagner et al., 1982; Bonfanti et al., 1989). This site needs JavaScript to work properly. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Exocytosis of Weibel-Palade Bodies: How to Unpack a Vascular Emergency Kit. Clearly, more work is required to establish a potential link between this zyxin/actomyosin network and the post-fusion actin rings, e.g. Microtubules and plus-end kinesin motors are necessary for long-range transport of WPBs from the TGN to peripheral locations in the cell, where a complex of MyRIP and Rab27A appears to mediate anchoring of WPBs to actin filaments.44 VWF secretion induced by Ca2+-elevating agonists is reported to be inhibited by disruption of microtubules with colchicine or nocodazole but potentiated by disruption of actin with cytochalasin E. In contrast, cAMP-mediated secretion is not affected by disruption of either microtubules or actin filaments, suggesting that only Ca2+-elevating agonists induce transport from the TGN to the cell membrane.44,67,68 In addition, Ca2+-elevating agonists can deplete the cell of almost all WPBs, whereas cAMP-elevating agonists selectively release a pool of mature WPBs that contain VWF but little or no P-selectin.69. Contribution: K.M.V., J.V., and J.E. How to Roll an Endothelial Cigar: The Biogenesis of Weibel-Palade Bodies. P-selectin and CD63 use different mechanisms for delivery to Weibel-Palade bodies. Biophys. The P-selectin lumenal domain alone is sufficient to direct incorporation into WPBs, possibly because it interacts with the DD3 domains of VWF.25 In addition, a YGVF motif in the P-selectin cytoplasmic tail can target heterologous proteins to WPBs. WPBs and -granules: more and more look-alike? surfactant-loaded lamellar bodies of alveolar epithelial cells (Miklavc et al., 2015), most likely require mechanical forces for efficient cargo expulsion. 2023 Feb 27;14:1094845. doi: 10.3389/fphys.2023.1094845. Three tubules stop halfway into the WPB (arrowheads) and 2 tubules display kinks (arrows). The biogenesis of WPB, their intracellular motility and their fusion with the plasma membrane are regulated by a complex interplay of proteins and lipids, involving Rab proteins and their effectors, cytoskeletal components as well as membrane tethering and fusion machineries. To cope with these challenges, endothelial cells have the remarkable capability of rapidly changing their surface properties from non-adhesive (supporting unrestricted blood flow) to adhesive (capturing circulating blood cells). Nguyen T. T. N., Koerdt S. N., Gerke V. (2020). Sci Rep. 2016 Aug 31;6:32473. doi: 10.1038/srep32473. and transmitted securely. (1982). Weibel Palade Bodies: Unique Secretory Organelles of Endothelial Cells that Control Blood Vessel Homeostasis Front Cell Dev Biol. Changes in the magnitude and quality of WPB exocytosis influence the plasma level of VWF and other prothrombotic and proinflammatory mediators, which in turn contribute to the pathophysiology of cardiovascular disorders. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. The tips of tubules frequently touch the WPB membrane, but the sides of tubules are separated from the membrane by a distance that often appears constant along the length of a tubule.3,23,47. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). MeSH A seemingly solitary nanovesicle is indicated with an arrow. VWF is synthesized in megakaryocytes and endothelial cells, and is stored and secreted from platelet alpha granules and Weibel-Palade bodies of endothelial cells. Scale bar represents 5 m. Before An official website of the United States government. (A) Immunofluorescence image of a stimulated HUVEC labeled with an antibody against VWF showing numerous VWF strings branching at the surface of the cell. Secretion of Weibel-Palade bodies observed in extra-alveolar vessels of rabbit lung. Zenner H. L., Collinson L. M., Michaux G., Cutler D. F. (2007). Proximity proteomics of endothelial Weibel-Palade bodies identifies novel regulator of von Willebrand factor secretion. by identifying the factor(s) promoting actin polymerisation into the ring/coat-like structures at fused WPB. A patient with the homozygous VWF N528S mutation did not respond to desmopressin (DDAVP; Rhone Poulenc Rorer, now Aventis Pharma) with an increase in plasma VWF, which suggests that failure to store mutant VWF N528S in transfected cells correlates with failure of storage and regulated secretion in vivo.54, Heterozygous D3 domain mutations C1157F and C1234W were identified in 2 families with VWD type 2A.55 When expressed in COS-7 cells, both mutant proteins were mostly retained in the ER and had severe defects in multimer assembly, which is often observed for VWF mutations at conserved Cys residues. Mainly factors identified in the recent years have been included. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Elongated WPB morphology is correlated to longer VWF strings with better adhesive properties. Careers. A helical model for tubular packing suggests that a 5-m tubule within a WPB could be composed of a single VWF multimer of approximately 3900 VWF subunits that would be 240 m long when fully extended.48 Much longer strings would be expected to consist of several VWF multimers. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. Aftiphilin and gamma-synergin are required for secretagogue sensitivity of Weibel-Palade bodies in endothelial cells. Traffic. Tuning the endothelial response: differential release of exocytic cargos from Weibel-Palade bodies. (PDF) WeibelPalade bodies at a glance - ResearchGate 14-16 Thus, the multimerization and regulated storage of VWF are important for initiation of clot formation following injury to a vessel. Epub 2005 Jun 14. Scale bar, 1 m. An official website of the United States government. Early endothelial changes in experimental primate atherosclerosis. Conte I. L., Cookson E., Hellen N., Bierings R., Mashanov G., Carter T. (2015).

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