Platelet dense granule secretion defects may obscure α-granule secretion mechanisms: evidence from Munc13-4–deficient platelets

Harper, Matthew T.; Bosch, Marion van den; Hers, Ingeborg; Poole, Alastair W.

doi:10.1182/blood-2014-12-618439

Cited by 28 publications

(33 citation statements)

References 5 publications

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“…However, it has recently been demonstrated that (1) NK cell cytotoxicity has a distinct immunoregulatory role in HLH disease, 19 and (2) Munc13-4 has a critical function in platelets and neutrophils. [20][21][22][23] By using an LV coding for a Munc13-4/GFP fusion protein, our present study demonstrated that gene transfer into murine HSCs resulted in transgene expression in all the hematopoietic lineages, including NK and myeloid cells. Thus, HSC gene correction (providing multilineage Munc13-4 expression) might be a valuable treatment option for FHL3 in patients.…”

Section: Discussionmentioning

confidence: 94%

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

et al. 2017

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Section: Discussionmentioning

confidence: 94%

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

et al. 2017

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“…When platelets are stimulated by agonists such as PAR4-activating peptide (PAR4-AP), Munc13-4 facilitates the pairing of SNAREs 25, 26, 46 involved with the fusion of secretory vesicles with the cell surface membrane. ADP has also been observed to trigger Munc13-4-independent granule secretion.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Trafficking, Localization, and Mobilization of Platelet-Borne Thiol Isomerases

Crescente

Pluthero

et al. 2016

ATVB

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Objective Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including PDI and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation and thrombus formation. In this study we examined for the first time the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets and identified the cellular events responsible for their movement to the platelet surface upon activation. Approach and Results Immunofluorescence microscopy (IFM) imaging was used to localize PDI and ERp57 in murine and human megakaryocytes at various developmental stages. IFM and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and SERCA3. IFM and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin), and in the presence or absence of membrane fusion mediated by Munc 13-4 (absent in platelets from Unc13dJinx mice). Conclusions Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes, and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not SNARE/Munc 13-4-dependent vesicular-plasma membrane fusion.

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“…59 The core comprises tightly packed, degranulated platelets encased in fibrin. 59 ADP released from dense granules regulates a-granule secretion, [60][61][62] forming dense regions that stabilize the platelet aggregate. 63 Concomitant release of polyP with ADP from dense granules suggests that it may be retained in these low-solute transport areas.…”

Section: Discussionmentioning

confidence: 99%

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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Key Points• PolyP significantly augments the plasminogen activator capacity of FXIIa.• Platelet-bound fibrin acts as a reservoir for plasminogen, FXII(a), and polyP.Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here, we investigate the contribution of polyP to the plasminogen activator function of aFXIIa. We show that both polyP 70 , of the chain length found in platelets (60-100 mer), and platelet-derived polyP significantly augment the plasminogen activation capacity of aFXIIa. PolyP 70 stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, aFXIIa remains bound to polyP 70 . Indeed, complex formation between polyP 70 and aFXIIa provides protection against autodegradation. Plasminogen activation by bFXIIa was minimal and not enhanced by polyP 70 , highlighting the importance of the anion binding site. PolyP 70 did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by aFXIIa. Accordingly, polyP 70 was found to bind to FXII, aFXIIa, and plasminogen, but not bFXIIa. Fibrin and polyP 70 acted synergistically to enhance aFXIIa-mediated plasminogen activation. The plasminogen activator activity of the aFXIIa-polyP 70 complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 2. Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, aFXIIa is a highly efficient and favorable plasminogen activator. Our data are the first to document a profibrinolytic function of platelet polyP. (Blood. 2016;128(24):2834-2845

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Platelet dense granule secretion defects may obscure α-granule secretion mechanisms: evidence from Munc13-4–deficient platelets

Cited by 28 publications

References 5 publications

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

Intracellular Trafficking, Localization, and Mobilization of Platelet-Borne Thiol Isomerases

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

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