Proteome of ubiquitin/MVB pathway: Possible involvement of iron-induced ubiquitylation of transferrin receptor in lysosomal degradation

Ryo Tachiyama, Daisuke Ishikawa, Masaki Matsumoto, Keiichi I. Nakayama, Tamotsu Yoshimori, Sadaki Yokota, Masaru Himeno, Yoshitaka Tanaka, Hideaki Fujita

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Ubiquitylation of membrane proteins triggers their endocytosis at the plasma membrane and subsequent lysosomal degradation through multivesicular bodies (MVBs). A dominant-negative mutant SKD1/Vps4B caused an accumulation of ubiquitylated membrane proteins in MVBs. We have identified 22 membrane proteins whose trafficking is potentially regulated by ubiquitylation. Nine of them, including transferrin receptor (TfR), are indeed ubiquitylated and/or accumulated in MVBs in the cells expressing mutant Vps4. While the recycling route and iron-regulated expression of TfR are well characterized, the mechanism by which the degradation of TfR is regulated is largely unknown. We show that an excess of iron enhances both TfR's ubiquitylation and degradation in lysosomes. Probably, the up-regulated expression of ferritin, an endogenous iron-chelating molecule, attenuated the iron-induced degradation of TfR. Exogenously introduced lysine-less TfR, compared to the wild-type one, showed resistance to the iron-induced ubiquitylation and degradation, when endogenous TfR, which most certainly heterodimerizes with exogenous ones, was depleted with siRNA. These data suggest that the iron-induced ubiquitylation and degradation of TfR along with MVB pathway physiologically plays an important role in iron homeostasis.

Original languageEnglish
Pages (from-to)448-466
Number of pages19
JournalGenes to Cells
Volume16
Issue number4
DOIs
Publication statusPublished - Apr 2011

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cell Biology

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