scholarly journals Munc13-4 Is an Effector of Rab27a and Controls Secretion of Lysosomes in Hematopoietic Cells

2005 ◽  
Vol 16 (2) ◽  
pp. 731-741 ◽  
Author(s):  
Maaike Neeft ◽  
Marnix Wieffer ◽  
Arjan S. de Jong ◽  
Gabriela Negroiu ◽  
Corina H.G. Metz ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Mast Cells ◽  
Genetic Disorder ◽  
Hematopoietic Cells ◽  
Lytic Granules ◽  
Secretory Lysosome ◽  
Griscelli Syndrome ◽  
Life Threatening ◽  
Lytic Granule ◽  
Secretory Lysosomes

Griscelli syndrome type 2 (GS2) is a genetic disorder in which patients exhibit life-threatening defects of cytotoxic T lymphocytes (CTLs) whose lytic granules fail to dock on the plasma membrane and therefore do not release their contents. The disease is caused by the absence of functional rab27a, but how rab27a controls secretion of lytic granule contents remains elusive. Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a disease phenotypically related to GS2. We show that Munc13-4 is a direct partner of rab27a. The two proteins are highly expressed in CTLs and mast cells where they colocalize on secretory lysosomes. The region comprising the Munc13 homology domains is essential for the localization of Munc13-4 to secretory lysosomes. The GS2 mutant rab27aW73G strongly reduced binding to Munc13-4, whereas the FHL3 mutant Munc13-4Δ608-611 failed to bind rab27a. Overexpression of Munc13-4 enhanced degranulation of secretory lysosomes in mast cells, showing that it has a positive regulatory role in secretory lysosome fusion. We suggest that the secretion defects seen in GS2 and FHL3 have a common origin, and we propose that the rab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells. Mutations in either of the two genes prevent formation of this complex and abolish secretion.

The munc13-4–rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1570-1578 ◽  
Author(s):  
Edo D. Elstak ◽  
Maaike Neeft ◽  
Nadine T. Nehme ◽  
Jarno Voortman ◽  
Marc Cheung ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Immune Cells ◽  
Total Internal Reflection ◽  
Target Cells ◽  
Binding Motif ◽  
Microscopy Imaging ◽  
Secretory Lysosome ◽  
Mast Cell Line ◽  
Type 3 ◽  
Secretory Lysosomes

Abstract Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27a-binding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13-4–rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4–rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells.

Adoptive Transfer of Nf1+/− Bone Marrow Is Sufficient for Neurofibroma Progression in Krox20;Nf1flox/flox Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3064-3064
Author(s):  
Fengchun Yang
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Tumor Microenvironment ◽  
Schwann Cells ◽  
Genetic Disorder ◽  
Hematopoietic Cells ◽  
Tumor Formation ◽  
Conditional Knockout ◽  
Axial Tomography

Abstract Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a GTPase activating protein for Ras called neurofibromin. NF1 is a genetic disorder that affects approximately 250,000 individuals in the US, Europe, and Japan alone. Neurofibromas, the hallmark of NF1, are complex tumors characterized by tumorigenic Schwann cells, neoangiogenesis, fibrosis, and degranulating mast cells. Studies in experimental models have emphasized the role of inflammatory cells in altering the microenvironment and facilitating malignant outgrowth. Similarly, Parada (Science, 2002) found that nullizygosity of Nf1 in Schwann cells of conditional knockout mice (Krox20;Nf1flox/flox) was necessary but not sufficient for neurofibroma formation and haploinsufficiency of Nf1 in lineages within the tumor microenvironment was required for neurofibroma progression. We previously provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters Ras activity and cell fates in mast cells (JEM, 2000, 2001) and identified a mechanism underlying the recruitment of mast cells to tumorigenic Schwann cells (JCI 2003). However, it remains unclear whether Nf1 +/− bone marrow derived hematopoietic cells can directly contribute to neurofibroma formation in vivo. To address this question, Nf1+/− or wildtype (WT) EGFP+ bone marrow (BM) was adoptively transferred into lethally irradiated Krox20;Nf1flox/flox mice and cohorts were followed prospectively for tumor formation using positron emission tomography and computerized axial tomography. Mice transplanted with Nf1+/− but not WT BM developed progressive enlargement of the trigeminal nerve, dorsal root ganglia, peripheral nerves, and motor paralysis similar to Krox20;Nf1flox/− mice that are haploinsufficient at Nf1 in all lineages of the tumor microenvironment. Postmortem analysis revealed that Krox20;Nf1flox/flox mice transplanted with Nf1+/− BM had cellular neurofibromas containing Schwann cells, fibroblasts, blood vessels and mast cells, which closely resembled the cellular architecture of human neurofibromas. Mice transplanted with WT BM did not develop neurofibromas. These studies establish that recruitment of Nf1 +/− BM derived cells to the neurofibroma microenvironment is directly linked to neurofibroma formation and progression. Given our observations, therapies which prevent both the recruitment and the tumor promoting functions of Nf1 +/− hematopoietic cells in neurofibroma formation are currently being tested in vivo as pre-clinical trials.

scholarly journals Munc13-4*rab27 complex tethers secretory lysosomes at the plasma membrane

2012 ◽  
Vol 5 (1) ◽  
pp. 64-67 ◽  
Author(s):  
Edo D. Elstak ◽  
Maaike Neeft ◽  
Nadine T. Nehme ◽  
Isabelle Callebaut ◽  
Geneviève de Saint Basile ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Secretory Lysosomes

Soluble proteins as modulators of the exocytotic reaction of permeabilised rat mast cells

1989 ◽  
Vol 94 (3) ◽  
pp. 585-591
Author(s):  
A. Koffer ◽  
B.D. Gomperts
Keyword(s):  
Plasma Membrane ◽  
Mast Cells ◽  
Soluble Proteins ◽  
The Other ◽  
Guanine Nucleotide ◽  
Cytoplasmic Proteins ◽  
Streptolysin O ◽  
Two Factors ◽  
Rat Mast Cells

This study addresses the question of the role of cytoplasmic proteins in exocytosis from permeabilised rat mast cells. We have used two different methods of cell permeabilisation (ATP4- and streptolysin O) to regulate the size of the plasma membrane lesions, and thus to dictate the rate and extent of efflux of the cytosolic proteins, and compared the secretory response of the two preparations. We report evidence for the existence of two factors present in the cytosol, which affect the exocytotic mechanism in opposing manners. One of these is required for the maintenance of cell responsiveness; it is retained for more than 120 min by ATP4- -permeabilised cells but lost within 60 min from cells permeabilised by streptolysin O. The other factor, which leaks immediately from cells treated from streptolysin O, but only gradually from cells treated with ATP4-, has the effect of suppressing the affinity for both Ca2+ and guanine nucleotide in the exocytotic reaction.

scholarly journals A Newly Discovered Genetic Disorder Associated With Life-Threatening Aortic Disease in a 6-Year-Old Boy

2020 ◽  
Vol 8 ◽  
pp. 232470962090923
Author(s):  
Mohanad Hamandi ◽  
Madison L. Bolin ◽  
Joy Fan ◽  
Allison T. Lanfear ◽  
Seth K. Woolbert ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Genetic Disorder ◽  
Aortic Disease ◽  
Connective Tissue Disorder ◽  
Aortic Aneurysms ◽  
Gene Variation ◽  
Life Threatening

Aortic aneurysms in children are rare and when present are usually caused by a connective tissue disorder. In this article, we present a case of multiple aortic aneurysms in an adolescent with a novel finding of a gene variation that is associated with aortic disease.

scholarly journals Hereditary angioedema: an update on causes, manifestations and treatment

2019 ◽  
Vol 80 (7) ◽  
pp. 391-398 ◽  
Author(s):  
Hilary J Longhurst ◽  
Konrad Bork
Keyword(s):  
Quality Of Life ◽  
Hereditary Angioedema ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Correct Diagnosis ◽  
Self Administration ◽  
Diagnosis And Management ◽  
Life Threatening ◽  
Short And Long Term

Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.

scholarly journals A Rare and Fatal Complication of a Self-Limiting Infection: A Case Report on Dengue Associated Hemophagocytic Lymphohistiocytosis

2019 ◽  
Vol 30 (2) ◽  
pp. 93-95
Author(s):  
Alvin Oliver Payus ◽  
Cheong Lei Wah ◽  
Syahrul Sazliyana Shaharir
Keyword(s):  
Case Report ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
De Novo ◽  
Medical Condition ◽  
Early Recognition ◽  
Genetic Disorder ◽  
Intravenous Methylprednisolone ◽  
Appropriate Treatment ◽  
Life Threatening

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. It can arise de novo as a result of an autosomal recessive genetic disorder, or in the background of an infection, malignancy or autoimmune disease. Dengue fever is one of the uncommon causes of infection related secondary HLH. Here, we present a case of a Dengue associated HLH which was successfully treated with intravenous methylprednisolone and immunoglobulin G. In conclusion, the purpose of this case report is to illustrate the importance of early recognition and prompt initiation of the appropriate treatment for HLH suspected patient whom otherwise has high mortality rate. Bangladesh J Medicine July 2019; 30(2) : 93-95

Recognition Sites for Microbes and Components of the Immune System on Human Mast Cells: Relationship to CD Antigens and Implications for Host Defense

2007 ◽  
Vol 20 (3) ◽  
pp. 421-434 ◽  
Author(s):  
M. Mayerhofer ◽  
K.J. Aichberger ◽  
S. Florian ◽  
P. Valent
Keyword(s):  
Immune System ◽  
Mast Cells ◽  
Host Defense ◽  
Specific Ige ◽  
Specific Cell ◽  
Surface Binding ◽  
Helminth Infections ◽  
Life Threatening ◽  
Current Article ◽  
Allergic Disorders

Traditionally, mast cells (MCs) have been considered to play an important role in allergic disorders and helminth infections. More recently, MCs have been implicated in a variety of different infectious diseases including life-threatening disorders caused by viruses and bacteria. Apart from recognition through specific IgE, MCs are considered to recognize such bacteria and viruses via specific cell surface binding sites. In addition, MCs interact with diverse components and cells of the immune system and thereby may facilitate the targeting and the elimination of invading microbes in the tissues. The current article provides an overview on MC antigens contributing to microbe recognition and targeting as an important element of natural host-defense.

scholarly journals Idiopathic Thrombocytopenic Purpura Misdiagnosed as Hereditary Angioedema

2015 ◽  
Vol 2015 ◽  
pp. 1-4
Author(s):  
Michelle Fog Andersen ◽  
Anette Bygum
Keyword(s):  
Idiopathic Thrombocytopenic Purpura ◽  
Hereditary Angioedema ◽  
Care Setting ◽  
Autosomal Dominant ◽  
Bleeding Episode ◽  
Genetic Disorder ◽  
Acute Attack ◽  
Autosomal Dominant Trait ◽  
Thrombocytopenic Purpura ◽  
Life Threatening

Hereditary angioedema is a rare, but potentially life-threatening genetic disorder that results from an autosomal dominant trait. It is characterized by acute, recurrent attacks of severe local edema, most commonly affecting the skin and mucosa. Swelling in hereditary angioedema patients does however not always have to be caused by angioedema but can relate to other concomitant disorders. In this report we are focusing on misdiagnosis in a patient with known hereditary angioedema, whose bleeding episode caused by idiopathic thrombocytopenic purpura was mistaken for an acute attack of hereditary angioedema. The case illustrates how clinicians can have difficulties in handling patients with rare diseases, especially in the emergency care setting.

scholarly journals Olopatadine Inhibits Exocytosis in Rat Peritoneal Mast Cells by Counteracting Membrane Surface Deformation

2015 ◽  
Vol 35 (1) ◽  
pp. 386-396 ◽  
Author(s):  
Asuka Baba ◽  
Masahiro Tachi ◽  
Yoshio Maruyama ◽  
Itsuro Kazama
Keyword(s):  
Plasma Membrane ◽  
Mast Cells ◽  
Lipid Bilayers ◽  
Surface Deformation ◽  
Lucifer Yellow ◽  
Membrane Surface ◽  
Water Soluble ◽  
Confocal Imaging ◽  
Peritoneal Mast Cells ◽  
Rat Peritoneal Mast Cells

Backgroud/Aims: Besides its anti-allergic properties as a histamine receptor antagonist, olopatadine stabilizes mast cells by inhibiting the release of chemokines. Since olopatadine bears amphiphilic features and is preferentially partitioned into the lipid bilayers of the plasma membrane, it would induce some morphological changes in mast cells and thus affect the process of exocytosis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of olopatadine and other anti-allergic drugs on the membrane capacitance (Cm) in rat peritoneal mast cells during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. Results: Low concentrations of olopatadine (1 or 10 µM) did not significantly affect the GTP-γ-S-induced increase in the Cm. However, 100 µM and 1 mM olopatadine almost totally suppressed the increase in the Cm. Additionally, these doses completely washed out the trapping of the dye on the cell surface, indicating that olopatadine counteracted the membrane surface deformation induced by exocytosis. As shown by electron microscopy, olopatadine generated inward membrane bending in mast cells. Conclusion: This study provides electrophysiological evidence for the first time that olopatadine dose-dependently inhibits the process of exocytosis in rat peritoneal mast cells. Such mast cell stabilizing properties of olopatadine may be attributed to its counteracting effects on the plasma membrane deformation in degranulating mast cells.

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