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.

A novel missense mutation in theHAX1gene in severe congenital neutropenia patients (Kostmann disease)

2009 ◽  
Vol 76 (6) ◽  
pp. 569-572 ◽  
Author(s):  
M Faiyaz-Ul-Haque ◽  
A Al-Jefri ◽  
HA Abalkhail ◽  
M Toulimat ◽  
MA Al-Muallimi ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Disease

Inherited Biallelic Loss-Of-Function Mutations In CSF3R Define a Novel Type Of Severe Congenital Neutropenia With Full Myeloid Cell Maturation and Refractoriness To RhG-CSF

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1025-1025
Author(s):  
Alexa Triot ◽  
Päivi M Järvinen ◽  
Juan I. Arostegui ◽  
Tomas Racek ◽  
Jacek Puchalka ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Morphological Variability ◽  
Myeloid Cell ◽  
Cell Maturation ◽  
Morphological Evidence ◽  
Compound Heterozygous ◽  
Neutrophil Granulocytes ◽  
Severe Congenital Neutropenia ◽  
Loss Of Function ◽  
Congenital Neutropenia

Abstract Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by defective production and viability of neutrophil granulocytes and predisposition to life-threatening bacterial infections. Currently, OMIM lists five defined monogenic SCN: SCN1 ELANE, SCN2 GFI1, SCN3 HAX1, SCN4 G6PC3. Here, we describe a novel SCN subtype (SCN6) caused by recessively-inherited loss-of-function mutations in the gene encoding the granulocyte colony-stimulating receptor (CSF3R). We have identified four affected children in two distinct families. Family A had a homozygous missense mutation in close proximity of the highly conserved WSXWS motif (c.922T, p.Arg308Cys) and family B had two compound heterozygous small deletions provoking frameshift mutations (p.Gly316fs and p.Gly415fs). Mutated G-CSFR p.Arg308Cys protein was characterized by perturbed N-glycosylation and aberrant localization to cell surface. G-CSF induced phosphorylation of STAT3 and STAT5 was greatly diminished. In contrast to other SCN subtypes, all patients had morphological evidence of full myeloid cell maturation in bone marrow. However, none of the patients responded to granulocyte colony-stimulating growth factor (GCSF) treatment in vivo, confirming aberrant GCSF-receptor dependent signaling. Our studies highlight the genetic and morphological variability of SCN and provide evidence both for functional importance and redundancy of G-CSFR-mediated signaling in human granulopoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Kostmann disease and other forms of severe congenital neutropenia

2021 ◽  
Author(s):  
Bengt Fadeel ◽  
Daniel Garwicz ◽  
Göran Carlsson ◽  
Bengt Sandstedt ◽  
Magnus Nordenskjöld
Keyword(s):  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Disease

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 Nuclear TRAF3 is a negative regulator of CREB in B cells

2016 ◽  
Vol 113 (4) ◽  
pp. 1032-1037 ◽  
Author(s):  
Nurbek Mambetsariev ◽  
Wai W. Lin ◽  
Laura L. Stunz ◽  
Brett M. Hanson ◽  
Joanne M. Hildebrand ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Critical Role ◽  
Adaptor Protein ◽  
B Cell Lymphoma ◽  
Camp Response Element Binding ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Littermate Control

The adaptor protein TNF receptor-associated factor 3 (TRAF3) regulates signaling through B-lymphocyte receptors, including CD40, BAFF receptor, and Toll-like receptors, and also plays a critical role inhibiting B-cell homoeostatic survival. Consistent with these findings, loss-of-function human TRAF3 mutations are common in B-cell cancers, particularly multiple myeloma and B-cell lymphoma. B cells of B-cell–specific TRAF3−/− mice (B-Traf3−/−) display remarkably enhanced survival compared with littermate control (WT) B cells. The mechanism for this abnormal homeostatic survival is poorly understood, a key knowledge gap in selecting optimal treatments for human B-cell cancers with TRAF3 deficiency. We show here for the first time to our knowledge that TRAF3 is a resident nuclear protein that associates with the transcriptional regulator cAMP response element binding protein (CREB) in both mouse and human B cells. The TRAF-C domain of TRAF3 was necessary and sufficient to localize TRAF3 to the nucleus via a functional nuclear localization signal. CREB protein was elevated in TRAF3−/− B cells, without change in mRNA, but with a decrease in CREB ubiquitination. CREB-mediated transcriptional activity was increased in TRAF3-deficient B cells. Consistent with these findings, Mcl-1, an antiapoptotic target of CREB-mediated transcription, was increased in the absence of TRAF3 and enhanced Mcl-1 was suppressed with CREB inhibition. TRAF3-deficient B cells were also preferentially sensitive to survival inhibition with pharmacologic CREB inhibitor. Our results identify a new mechanism by which nuclear TRAF3 regulates B-cell survival via inhibition of CREB stability, information highly relevant to the role of TRAF3 in B-cell malignancies.

scholarly journals The Signaling Adaptor Protein CD3ζ Is a Negative Regulator of Dendrite Development in Young Neurons

2008 ◽  
Vol 19 (6) ◽  
pp. 2444-2456 ◽  
Author(s):  
Stéphane J. Baudouin ◽  
Julie Angibaud ◽  
Gildas Loussouarn ◽  
Virginie Bonnamain ◽  
Akihiro Matsuura ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Development ◽  
Adaptor Protein ◽  
Neurite Growth ◽  
Negative Regulator ◽  
Cultured Neurons ◽  
Loss Of Function ◽  
Dendrite Development ◽  
Neuronal Functions ◽  
Immunohistochemical Analyses

A novel idea is emergxsing that a large molecular repertoire is common to the nervous and immune systems, which might reflect the existence of novel neuronal functions for immune molecules in the brain. Here, we show that the transmembrane adaptor signaling protein CD3ζ, first described in the immune system, has a previously uncharacterized role in regulating neuronal development. Biochemical and immunohistochemical analyses of the rat brain and cultured neurons showed that CD3ζ is mainly expressed in neurons. Distribution of CD3ζ in developing cultured hippocampal neurons, as determined by immunofluorescence, indicates that CD3ζ is preferentially associated with the somatodendritic compartment as soon as the dendrites initiate their differentiation. At this stage, CD3ζ was selectively concentrated at dendritic filopodia and growth cones, actin-rich structures involved in neurite growth and patterning. siRNA-mediated knockdown of CD3ζ in cultured neurons or overexpression of a loss-of-function CD3ζ mutant lacking the tyrosine phosphorylation sites in the immunoreceptor tyrosine-based activation motifs (ITAMs) increased dendritic arborization. Conversely, activation of endogenous CD3ζ by a CD3ζ antibody reduced the size of the dendritic arbor. Altogether, our findings reveal a novel role for CD3ζ in the nervous system, suggesting its contribution to dendrite development through ITAM-based mechanisms.

HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)

2006 ◽  
Vol 39 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Christoph Klein ◽  
Magda Grudzien ◽  
Giridharan Appaswamy ◽  
Manuela Germeshausen ◽  
Inga Sandrock ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Disease
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