ATP7B-maintained copper stores in myeloid progenitors are required for functional maturation of neutrophils

Authors : Som Dev, Yu Wang, Moonjung Jung, Yingze Ma, Sepehr Mani, Ekaterina Kabin, Ridzky Yuda, Yixuan Dong, Martina Ralle, James P. Hamilton, Svetlana Lutsenko

Journal: Cell Reports, Vol 45 (2), 2026

“Copper homeostasis in neutrophil maturation
” — Copper (Cu) is essential for innate immunity; however, how neutrophils regulate Cu homeostasis to support their functions remains unclear. We found that myeloid progenitors express abundant Cu-transporter ATP7B targeted to distinct vesicles and store Cu in vesicles. During neutrophil differentiation, ATP7B is downregulated, whereas ATP7A, LOXL2, and SLC31A2 are induced, suggesting a coordinated switch from Cu storage to utilization. As mature neutrophils exit the bone marrow, cellular Cu levels drop markedly, indicating Cu release during late maturation or egress. Myeloid-specific deletion of Atp7b in mice uncouples lineage commitment from functional maturation: Atp7b-deficient cells differentiate into neutrophils but fail to mature fully, showing more mitochondria, fewer lysosome-like structures, lower abundance of Cebp-ε and Ngal, reduced tubulin levels, and disrupted microtubules. Following lipopolysaccharide injection, Atp7b-deficient bone marrow releases fewer neutrophils into the bloodstream. Together, these findings reveal a previously unrecognized role of the Cu-transport network in neutrophil maturation and egress.

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