scholarly journals JAGN1, tetraspanins, and Erv proteins: is common topology indicative of common function in cargo sorting?

2020 ◽  
Vol 319 (4) ◽  
pp. C667-C674
Author(s):  
Peyton E. VanWinkle ◽  
Felicia Parish ◽  
Yvonne J. K. Edwards ◽  
Elizabeth Sztul
Keyword(s):  
Endoplasmic Reticulum ◽  
Sequence Similarity ◽  
Neutrophil Function ◽  
Membrane Topology ◽  
Binding Motif ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cellular Processes ◽  
Plant Phylogeny ◽  
Endoplasmic Reticulum Protein

The endoplasmic reticulum protein Jagunal (JAGN1) was first identified as a requirement for Drosophila melanogaster oocyte development. Subsequent studies in human patients linked mutations in JAGN1 to severe congenital neutropenia, as well as a broad range of additional symptoms, suggesting that JAGN1 function is required in many tissues. Moreover, JAGN1 orthologs are found throughout animal and plant phylogeny, suggesting that JAGN1 supports fundamental cellular processes not restricted to egg development or neutrophil function. JAGN1 lacks sequence similarity or recognizable domains other than a coatomer protein complex I-binding motif, and its cellular function is currently unknown. JAGN1 shares a tetraspanning membrane topology with two families of known cargo transporters: the tetraspanins and the endoplasmic reticulum vesicle (Erv) proteins. Herein, we discuss the similarities between JAGN1, tetraspanins, and Ervs and, based on those, suggest a role for JAGN1 in facilitating the traffic of cell-restricted and ubiquitously expressed proteins at the endoplasmic reticulum-Golgi interface.

scholarly journals Hax1 regulates neutrophil adhesion and motility through RhoA

2011 ◽  
Vol 193 (3) ◽  
pp. 465-473 ◽  
Author(s):  
Peter J. Cavnar ◽  
Erwin Berthier ◽  
David J. Beebe ◽  
Anna Huttenlocher
Keyword(s):  
Adaptor Protein ◽  
Neutrophil Function ◽  
Negative Regulator ◽  
Neutrophil Adhesion ◽  
Severe Congenital Neutropenia ◽  
Loss Of Function ◽  
Congenital Neutropenia ◽  
Rhoa Activity ◽  
Protein X ◽  
Kostmann Disease

Kostmann disease is an inherited severe congenital neutropenia syndrome associated with loss-of-function mutations in an adaptor protein HS1-associated protein X-1 (Hax1). How Hax1 regulates neutrophil function remains largely unknown. In this paper, we use ribonucleic acid interference to deplete Hax1 in the neutrophil-like cell line PLB-985 and identify Hax1 as a negative regulator of integrin-mediated adhesion and chemotaxis. Using microfluidics, we show that depletion of Hax1 impairs neutrophil uropod detachment and directed migration. Hax1-deficient cells also display increased integrin-mediated adhesion and reduced RhoA activity. Moreover, depletion of RhoA induces increased neutrophil adhesion and impaired migration, suggesting that Hax1 regulates neutrophil adhesion and chemotaxis through RhoA. Accordingly, activation of RhoA is sufficient to rescue adhesion of Hax1-deficient neutrophils. Together, our findings identify Hax1 as a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA.

scholarly journals Severe Congenital Neutropenia Due To G6PC3 Deficiency Case Series of Five Patients and Literature Review

2021 ◽  
Author(s):  
Natalia Female Vélez-Tirado ◽  
Marco Antonio Yamazaki-Nakashimada ◽  
Enrique Lopez Valentín ◽  
Armando Partida-Gaytan ◽  
Selma C Scheffler-Mendoza ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Literature Review ◽  
Endoplasmic Reticulum Stress ◽  
Case Series ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
The Past ◽  
Genetic Features ◽  
Venous Pattern ◽  
Recurrent Pyogenic Infections

Abstract Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern, and cardiovascular and urogenital malformations, caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We describe five new cases from Mexico, and review 89 more patients reported in the past decade, to delineate the most frequent laboratory and genetic features, their treatment, and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.

A Novel Clinical Syndrome Associating Severe Congenital Neutropenia and Complex Developmental Aberrations Caused by Deficiency of G6PC3

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5-5
Author(s):  
Kaan Boztug ◽  
Giridharan Appaswamy ◽  
Angel Ashikov ◽  
Alejandro A Schäffer ◽  
Ulrich Salzer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bacterial Infections ◽  
Myeloid Cells ◽  
Missense Mutations ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hematopoietic Stem ◽  
A Genome ◽  
Increased Susceptibility

Abstract We here describe a previously unrecognized nosological entity in 12 patients from 8 unrelated pedigrees. All patients presented with severe congenital neutropenia and severe invasive bacterial infections. In addition, patients had a variety of additional syndromic features such as congenital heart disease (8/12), urogenital malformations (5/12), inner ear hearing loss (2/12), and myopathy (1/12). Furthermore, most patients (10/12) showed increased visibility/angiectasia of subcutaneous veins. The bone marrow smear was characterized by a typical “maturation arrest” due to premature apoptosis of mature neutrophils. Similar to Kostmann’s disease secondary to mutations in HAX1, myeloid cells from patients with this novel syndrome showed increased susceptibility to apoptosis. Myeloid progenitor cells revealed an abnormally enlarged rough endoplasmic reticulum and increased endoplasmic reticulum stress evidenced by increased expression of BiP. A genome-wide linkage study, performed in two consanguineous pedigrees, gave statistical evidene of a linkage interval on chromosome 17q21 (LOD score 5.74). We identified homozygous missense mutations in G6PC3, a ubiquitously expressed paralog of glucose-6-phosphatase. Biochemical studies confirmed deficient enzymatic activity. Using retroviral G6PC3-gene transfer into primary hematopoietic stem cells and in vitro differentiation into myeloid cells, the phenotype of increased susceptibility to apoptosis could be reverted. Eight distinct biallelic mutations were found, including missense and nonsense mutations. G6PC3-deficient myeloid cells showed a predominance of the unphosphorylated form of GSK3beta, a key molecule controlling cellular differentiation and apoptosis. As a consequence of increased GSK3beta activity, increased phosphorylation of the antiapoptotic molecule Mcl1 was detected, explaining increased susceptibility to apoptosis in neutrophils. In summary, our study describes a novel disease, determines its molecular etiology, and sheds light on the role of glucose-dependent pathways in controlling the homeostasis of the endoplasmic reticulum and control of apoptosis.

scholarly journals Severe congenital neutropenia due to G6PC3 deficiency. Case series of five patients and literature review

2021 ◽  
Author(s):  
Natalia Velez-Tirado ◽  
Marco Antonio Yamazaki-Nakashimada ◽  
Enrique Lopez Valentín ◽  
Armando Partida-Gaytan ◽  
Selma C Scheffler-Mendoza ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Literature Review ◽  
Endoplasmic Reticulum Stress ◽  
Case Series ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
The Past ◽  
Genetic Features ◽  
Venous Pattern ◽  
Recurrent Pyogenic Infections

Abstract Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern, and cardiovascular and urogenital malformations, caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We describe five new cases from Mexico, and review 89 more patients reported in the past decade, to delineate the most frequent laboratory and genetic features, their treatment, and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.

An Ultra-Structural Study of Human Melanoma in Vivo and Vitro

1976 ◽  
Vol 34 ◽  
pp. 258-259
Author(s):  
James R. Gaylor ◽  
Fredda Schafer ◽  
Robert E. Nordquist
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Protein Aggregation ◽  
Structural Study ◽  
Human Melanoma ◽  
Protein Matrix ◽  
Early Form ◽  
Endoplasmic Reticulum Protein ◽  
Mitochondrial Origin

Several theories on the origin of the melanosome exist. These include the Golgi origin theory, in which a tyrosinase-rich protein is "packaged" by the Golgi apparatus, thus forming the early form of the melanosome. A second theory postulates a mitochondrial origin of melanosomes. Its author contends that the melanosome is a modified mitochondria which acquires melanin during its development. A third theory states that a pre-melanosome is formed in the smooth or rough endoplasmic reticulum. Protein aggregation is suggested by one author as a possible source of the melanosome. This fourth theory postulates that the melanosome originates when the protein products of several genetic loci aggregate in the cytoplasm of the melanocyte. It is this protein matrix on which the melanin is deposited. It was with these theories in mind that this project was undertaken.

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