An essential role for the Zn2+ transporter ZIP7 in B cell development

Anzilotti, Consuelo; Swan, David J.; Boisson, Bertrand; Deobagkar-Lele, Mukta; Oliveira, Cathy; 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, Ben; McGrath, John A.; Przyborski, Stefan; Koref, Mauro Santibanez; Tangye, Stuart G.; Werner, Andreas; Rutter, Guy A.; Padilla-Parra, Sergi; Casanova, Jean-Laurent; Cornall, Richard J.; Conley, Mary Ellen; Hambleton, Sophie

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 Zn2+ in modulating B cell receptor signal strength and positive selection.

Citation

Anzilotti, C., Swan, D. J., Boisson, B., Deobagkar-Lele, M., Oliveira, C., Chabosseau, P., …Hambleton, S. (2019). An essential role for the Zn2+ transporter ZIP7 in B cell development. Nature Immunology, 20, 350-361. https://doi.org/10.1038/s41590-018-0295-8

• Journal Article Type: Article
• Acceptance Date: Dec 5, 2018
• Online Publication Date: Feb 4, 2019
• Publication Date: Feb 4, 2019
• Deposit Date: Jan 15, 2019
• Publicly Available Date: Aug 4, 2019
• Journal: Nature Immunology
• Print ISSN: 1529-2908
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Pages: 350-361
• DOI: https://doi.org/10.1038/s41590-018-0295-8
• Public URL: https://durham-repository.worktribe.com/output/1305211