A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration

Avery, Lyndsay; Robertson, Tanner F.; Wu, Christine F.; Roy, Nathan H.; Chauvin, Samuel D.; Perkey, Eric; Vanderbeck, Ashley; Maillard, Ivan; Burkhardt, Janis K.

doi:10.3389/fimmu.2021.726406

Cited by 3 publications

(2 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One X-linked moesin-associated immunodeficiency (X-MAID) has been identified and is characterized by a primary immunodeficiency associated with severe lymphopenia leading to recurrent infections. X-MAID is caused by a single-point mutation leading to a R171W amino acid change in moesin (moesinR171W) [171]. In fact, a mouse model with global expression of moesinR171W exhibited lymphopenia, but it was still characterized by systemic inflammation [171].…”

Section: Moesin In Mast Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Potential Role of Moesin in Regulating Mast Cell Secretion

Kempuraj

2023

IJMS

View full text Add to dashboard Cite

Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. The Ezrin/Radixin/Moesin (ERM) family of proteins is involved in linking cell surface-initiated signaling to the actin cytoskeleton. However, how ERMs may regulate secretion from mast cells is still poorly understood. ERMs contain two functional domains connected through a long α-helix region, the N-terminal FERM (band 4.1 protein-ERM) domain and the C-terminal ERM association domain (C-ERMAD). The FERM domain and the C-ERMAD can bind to each other in a head-to-tail manner, leading to a closed/inactive conformation. Typically, phosphorylation on the C-terminus Thr has been associated with the activation of ERMs, including secretion from macrophages and platelets. It has previously been shown that the ability of the so-called mast cell “stabilizer” disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, which was subsequently shown to be moesin, a member of ERMs. Interestingly, the phosphorylation of moesin during the inhibition of mast cell secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and render it inaccessible to binding to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal-associated proteins (SNAPs) critical for exocytosis. Using confocal microscopic imaging, we showed moesin was found to colocalize with actin and cluster around secretory granules during inhibition of secretion. In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion of allergic and inflammatory mediators from mast cells.

show abstract

Section: Moesin In Mast Cellsmentioning

confidence: 99%

“…X-MAID is caused by a single-point mutation leading to a R171W amino acid change in moesin (moesinR171W) [171]. In fact, a mouse model with global expression of moesinR171W exhibited lymphopenia, but it was still characterized by systemic inflammation [171].…”

Section: Moesin In Mast Cellsmentioning

confidence: 99%

Potential Role of Moesin in Regulating Mast Cell Secretion

Kempuraj

2023

IJMS

View full text Add to dashboard Cite

show abstract

Characterization of thymic architecture and lymphocyte populations in X-MAID due to an underlying pathogenic moesin mutation

Al Ghamdi,

Vong,

M. Roifman

et al. 2024

LymphoSign Journal

View full text Add to dashboard Cite

Background: X-linked Moesin Associated Immunodeficiency (X-MAID) is a combined immunodeficiency caused by deficiency in the moesin protein. Moesin, which is encoded by the MSN gene, is part of the ezrin-radixin-moesin (ERM) family of transmembrane proteins that interact with the actin cytoskeleton and regulate the shape and migration of cells. Deficiency of moesin is associated with aberrant T cell migration and inadequate immune synapse formation, leading to significant immunodeficiency and recurrent infections. While the clinical presentation of XMAID is diverse, to date, no thymus histopathology findings have been reported. Aim: Describe the thymus histopathology of a patient with X-MAID. Results: Our patient is a 10-year-old male who presented early in life with recurrent infections, dysmorphic features, and severe pulmonary venous stenosis which required a double lung transplant at the age of 4 years. Prior to transplant, he was referred to Immunology for assessment and was subsequently found to harbour a hemizygous variant in the MSN gene (c.278dupT; L93FfsX21). Thymus histophathology findings showed significant cortical atrophy and dysplasia, and was accompanied by reduction in CD3+ cells in the cortex. Abnormally low numbers of suppressor T cells and T helper cells in the thymic cortex and medulla were noted. Conclusion: Thymic findings in X-MAID can include cortical atrophy, dysplasia, and decreased cellularity. This provides further evidence for the importance of moesin on T cell development and migration in the thymus. Statement of Novelty: Description of thymus histopathology in a patient with X-MAID

show abstract

Potential Role of Moesin in Regulating Mast Cell Secretion

Theoharides¹,

Kempuraj²

2023

Preprint

View full text Add to dashboard Cite

Mast cells play a critical role in allergies and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. We previously showed that the ability of the so called mast cell “stabilizer” disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, and subsequently showed this protein to be moesin, a member of the Ezrin/Radixin/Moesin (ERM) family of proteins, which are involved in linking cell surface-initiated signaling to the actin cytoskeleton. Unlike phosphorylation on the C-terminus Thr558 associated with activation of ERMs, including secretion from macrophages and platelets, we showed that phosphorylation of moesin during inhibition of secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and remain inaccessible to bind to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal associated proteins (SNAPs). Using Confocal microscopic imaging, we showed moesin to colocalize with actin and cluster around secretory granules during inhibition of secretion, In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion from mast cells.

show abstract

A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration

Cited by 3 publications

References 44 publications

Potential Role of Moesin in Regulating Mast Cell Secretion

Potential Role of Moesin in Regulating Mast Cell Secretion

Characterization of thymic architecture and lymphocyte populations in X-MAID due to an underlying pathogenic moesin mutation

Potential Role of Moesin in Regulating Mast Cell Secretion

Contact Info

Product

Resources

About