An essential role for the Zn transporter ZIP7 in B cell development.
Anzilotti, Consuelo, Swan, David, Boisson, Bertrand, Deobagkar-Lele, Mukta, Oliveira, Catarina, Chabosseau, Pauline, Engelhardt, Karin R, Xu, Xijin, Chen, Rui, Alvarez, Luis, Berlinguer-Palmini, Rolando, Bull, Katherine R, Cawthorne, Eleanor, Cribbs, Adam P, Crockford, Tanya L, Dang, Tarana Singh, Fearn, Amy, Fenech, Emma J, de Jong, Sarah J, Lagerholm, B Christoffer, Ma, Cindy S, Sims, David, van den Berg, Bert, Xu, Yaobo, Cant, Andrew J, Kleiner, Gary, Leahy, T Ronan, de la Morena, M Teresa, Puck, Jennifer M, Shapiro, Ralph S, van der Burg, Mirjam, Chapman, J Ross, Christianson, John C, Davies, Benjamin, McGrath, John A, Przyborski, Stefan, Santibanez Koref, Mauro, Tangye, Stuart G, Werner, Andreas, Rutter, Guy A, Padilla-Parra, Sergi, Casanova, Jean-Laurent, Cornall, Richard J, Conley, Mary Ellen and Hambleton, Sophie
(2019)
An essential role for the Zn transporter ZIP7 in B cell development.
Nature immunology, 20 (3).
pp. 350-361.
ISSN 1529-2916
Abstract
Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn in modulating B cell receptor signal strength and positive selection.
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| Date Deposited: 05 Oct 2023 12:50 |
| Last Modified: 24 Apr 2024 12:28 |
Contributors
| Author: |
David Swan
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| Author: |
Consuelo Anzilotti
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| Author: |
Bertrand Boisson
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| Author: |
Mukta Deobagkar-Lele
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| Author: |
Catarina Oliveira
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| Author: |
Pauline Chabosseau
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| Author: |
Karin R Engelhardt
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| Author: |
Xijin Xu
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| Author: |
Rui Chen
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| Author: |
Luis Alvarez
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| Author: |
Rolando Berlinguer-Palmini
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| Author: |
Katherine R Bull
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| Author: |
Eleanor Cawthorne
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| Author: |
Adam P Cribbs
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| Author: |
Tanya L Crockford
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| Author: |
Tarana Singh Dang
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| Author: |
Amy Fearn
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| Author: |
Emma J Fenech
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| Author: |
Sarah J de Jong
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| Author: |
B Christoffer Lagerholm
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| Author: |
Cindy S Ma
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| Author: |
David Sims
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| Author: |
Bert van den Berg
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| Author: |
Yaobo Xu
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| Author: |
Andrew J Cant
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| Author: |
Gary Kleiner
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| Author: |
T Ronan Leahy
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| Author: |
M Teresa de la Morena
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| Author: |
Jennifer M Puck
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| Author: |
Ralph S Shapiro
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| Author: |
Mirjam van der Burg
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| Author: |
J Ross Chapman
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| Author: |
John C Christianson
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| Author: |
Benjamin Davies
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| Author: |
John A McGrath
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| Author: |
Stefan Przyborski
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| Author: |
Mauro Santibanez Koref
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| Author: |
Stuart G Tangye
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| Author: |
Andreas Werner
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| Author: |
Guy A Rutter
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| Author: |
Sergi Padilla-Parra
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| Author: |
Jean-Laurent Casanova
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| Author: |
Richard J Cornall
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| Author: |
Mary Ellen Conley
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| Author: |
Sophie Hambleton
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