Membrane-associated RING-CH (MARCH) 8 mediates the ubiquitination and lysosomal degradation of the transferrin receptor

Hideaki Fujita, Yukie Iwabu, Kenzo Tokunaga, Yoshitaka Tanaka

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

The transferrin receptor (TfR) mediates the uptake of transferrin (Tf)-bound iron from the plasma into the cells of peripheral tissues. The TfR continuously recycles between the plasma membrane and early/recycling endosomes. TfR expression is tightly controlled by the intracellular iron concentration through the regulation of TfR mRNA stability. However, much less is known about the mechanism by which TfR is degraded in cells. Previously, we reported a correlation between TfR ubiquitination and its iron-induced lysosomal degradation. The identification and characterization of a specific ubiquitin ligase for TfR is important in understanding the mechanism of iron homeostasis. Here, we show that membrane-associated RING-CH (MARCH) 8 ubiquitinates TfR and promotes its lysosomal degradation. Similar to other RING-type ubiquitin ligases, the RING-CH domain of MARCH8, which is located in the N-terminal cytoplasmic domain, is essential for the ubiquitination and downregulation of TfR. MARCH8 specifically recognizes the transmembrane domain of TfR and mediates ubiquitination of its cytoplasmic domain. In addition, the six-amino-acid sequence located in the Cterminal domain of MARCH8, which is highly conserved among different species, is required for the downregulation of TfR. Finally, and most importantly, TfR expression was markedly increased by siRNA-mediated knockdown of endogenous MARCH8. These findings demonstrate that the endogenous level of MARCH8 regulates TfR protein turnover through the downregulation and ubiquitination of TfR.

Original languageEnglish
Pages (from-to)2798-2809
Number of pages12
JournalJournal of cell science
Volume126
Issue number13
DOIs
Publication statusPublished - Jul 2013

All Science Journal Classification (ASJC) codes

  • Cell Biology

Fingerprint Dive into the research topics of 'Membrane-associated RING-CH (MARCH) 8 mediates the ubiquitination and lysosomal degradation of the transferrin receptor'. Together they form a unique fingerprint.

Cite this