2.A.5.4.15
Zinc/iron/manganese/cadmium/selenium transporter ZIP8 (BCG-induced integral membrane protein in monocyte clone 103 protein) (Solute carrier family 39 member 8 (SLC39A8; Zrt- and Irt-like protein 8) (Jenkitkasemwong et al. 2012).  Functions in Cd²⁺ and Mn²⁺ uptake, cell toxicity and hypertension (Zhang et al. 2015). Also transports selenium (Liang et al. 2021). Four amino acid residues, V33, G38, S335, and I340 of hZIP8 are mutated in patients with congenital disorders of glycosylation (CDG), caused by low blood Mn²⁺ levels (Fujishiro et al. 2022). Among the four mutations observed in ZIP8-mutated CDG patients, the S335T and I340N mutations in TMS5 abolished Mn²⁺- and Cd²⁺-transport activity, while V33M and G35R mutations did not. Artificial mutations in the metal-binding motif EEXXH in TMS5, which exists in most ZIP transporters, abolished the Mn²⁺- and Cd²⁺-transport activity of hZIP8 (Fujishiro et al. 2022). Loss of hepatic manganese transporter ZIP8 disrupts serum transferrin glycosylation and the glutamate-glutamine cycle (Powers et al. 2023). ZIP8 plays a role in systemic iron homeostasis but does not modulate the severity of inflammatory lung injury or the host defense against a common bacterial cause of pneumonia (Zhang et al. 2023). Neuronal SLC39A8 deficiency impairs cerebellar development by altering manganese homeostasis (Choi et al. 2024).