title: 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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and.
authors.forename: Ningning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and.
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Zhang
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and.
authors.forename: Christal
authors.initials: C
authors.lastname: Worthen
authors.affiliation: Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611.
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Knutson
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and ennsca@ohsu.edu.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Enns
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D006031:Glycosylation; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: D027682:Cation Transport Proteins; C497524:SLC39A14 protein, human; D007501:Iron; D046988:Proteasome Endopeptidase Complex
keywords: SLC39A14; hereditary hemochromatosis