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Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9175-80. doi: 10.1073/pnas.1405355111. Epub 2014 Jun 9.

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

Author information

1
Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and.
2
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611.
3
Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and ennsca@ohsu.edu.

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.

KEYWORDS:

SLC39A14; hereditary hemochromatosis

PMID:
24927598
PMCID:
PMC4078863
DOI:
10.1073/pnas.1405355111
[Indexed for MEDLINE]
Free PMC Article
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