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

Ningning Zhao, An-Sheng Zhang, Christal Worthen, Mitchell D. Knutson, Caroline Enns

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9175-9180
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
StatePublished - Jun 24 2014

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Membrane Transport Proteins
Glycosylation
Iron
Metals
Cell Membrane
Proteolysis
Proteasome Endopeptidase Complex
Endocytosis
Membranes
Blood Proteins
Membrane Proteins
Endoplasmic Reticulum-Associated Degradation
Multivesicular Bodies
Asparagine
Lysosomes
Endoplasmic Reticulum

Keywords

  • Hereditary hemochromatosis
  • SLC39A14

ASJC Scopus subject areas

  • General

Cite this

An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14. / Zhao, Ningning; Zhang, An-Sheng; Worthen, Christal; Knutson, Mitchell D.; Enns, Caroline.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 25, 24.06.2014, p. 9175-9180.

Research output: Contribution to journalArticle

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