An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14

Abstract

Protein degradation is instrumental in regulating cellular function. Plasma membrane proteins targeted for degradation are internalized and sorted to multivesicular bodies, which fuse with lysosomes, where they are degraded. ZIP14 is a newly identified iron transporter with multitransmembrane domains. In an attempt to dissect the molecular mechanisms by which iron regulates ZIP14 levels, we found that ZIP14 is endocytosed, extracted from membranes, deglycosylated, and degraded by proteasomes. This pathway did not depend on the retrograde trafficking to the endoplasmic reticulum and thus did not involve the well-defined endoplasmic reticulum-associated protein degradation pathway. Iron inhibited membrane extraction of internalized ZIP14, resulting in higher steady-state levels of ZIP14. Asparagine-linked (N-linked) glycosylation of ZIP14, particularly the glycosylation at N102, was required for efficient membrane extraction of ZIP14 and therefore is necessary for its iron sensitivity. These findings highlight the importance of proteasomes in the degradation of endocytosed plasma membrane proteins.

Post-translational modification of the interferon-gamma receptor alters its stability and signaling

“…Several mature receptors have been demonstrated to be subject to proteasomal degradation by various mechanisms including metalloproteinase cleavage and internalization followed by membrane extraction [25,26]. Glycosylation, in some circumstances, appeared to be required for ubiquitination and proteasomal degradation [27]. In separate studies, we demonstrate that IFNGR1 glycosylation does not impact stability of the receptor (Supplementary Figure S3).…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…The ability of ZIP14 to transport a transferrin unbound iron transport (NTBI) is thought to physiologically contribute to iron homeostasis (22), because hereditary hemochromatosis protein HFE inhibits iron uptake via downregulation of ZIP14 (120). Iron deficiency promotes ZIP14 degradation through proteasomes (463).…”

Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease

“…By contrast, ZIP8 and ZIP14 mRNA stability is unaffected by iron, and ZIP protein levels are positively correlated with iron status, in that iron loading increases ZIP8/14 protein amount whereas iron deficiency decreases protein amount [12,18]. …”