An essential role for the Zn 2+ transporter ZIP7 in B cell development

Consuelo Anzilotti, David J. Swan, Bertrand Boisson, Mukta Deobagkar-Lele, Catarina Oliveira, Pauline Chabosseau, Karin R. Engelhardt, Xijin Xu, Rui Chen, Luis Alvarez, Rolando Berlinguer-Palmini, Katherine R. Bull, Eleanor Cawthorne, Adam P. Cribbs, Tanya L. Crockford, Tarana Singh Dang, Amy Fearn, Emma J. Fenech, Sarah J. de Jong, B. Christoffer LagerholmCindy S. Ma, David Sims, Bert van den Berg, Yaobo Xu, Andrew J. Cant, Gary Kleiner, T. Ronan Leahy, M. Teresa de la Morena, Jennifer M. Puck, Ralph S. Shapiro, Mirjam van der Burg, J. Ross Chapman, John C. Christianson, Benjamin Davies, John A. McGrath, Stefan Przyborski, Mauro Santibanez Koref, Stuart G. Tangye, Andreas Werner, Guy A. Rutter, Sergi Padilla-Parra, Jean Laurent Casanova, Richard J. Cornall, Mary Ellen Conley, Sophie Hambleton

Research output: Contribution to journalArticle

20 Scopus citations

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 2+ in modulating B cell receptor signal strength and positive selection.

Original languageEnglish (US)
Pages (from-to)350-361
Number of pages12
JournalNature immunology
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Anzilotti, C., Swan, D. J., Boisson, B., Deobagkar-Lele, M., Oliveira, C., Chabosseau, P., Engelhardt, K. R., Xu, X., Chen, R., Alvarez, L., Berlinguer-Palmini, R., Bull, K. R., Cawthorne, E., Cribbs, A. P., Crockford, T. L., Dang, T. S., Fearn, A., Fenech, E. J., de Jong, S. J., ... Hambleton, S. (2019). An essential role for the Zn 2+ transporter ZIP7 in B cell development Nature immunology, 20(3), 350-361. https://doi.org/10.1038/s41590-018-0295-8