The small-molecule iron transport inhibitor ferristatin/NSC306711 promotes degradation of the transferrin receptor.
Iron delivery by transferrin (Tf) is accomplished through clathrin-mediated endocytosis of Tf receptors. The small molecule NSC306711 inhibits iron uptake from the Tf-TfR pathway. Here we show that the drug's mechanism of action is to induce internalization and degradation of unoccupied Tf receptors through an unexpected endocytic pathway. Unlike classical clathrin-mediated Tf receptor endocytosis, internalization promoted by NSC306711 is independent of clathrin and dynamin, and is sensitive to the cholesterol-depleting agents filipin and nystatin. The finding of this cholesterol-dependent Tf receptor internalization pathway through use of the small-molecule inhibitor sheds light on the pleiotropic nature of membrane trafficking dynamics and adds a complex dimension to our understanding of receptor regulation. Because of its unusual properties to inhibit iron uptake, we refer to NSC306711 as "ferristatin."
Horonchik
Lior
L
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Wessling-Resnick
Marianne
M
D001692:Biological Transport; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000737:chemistry; D002966:Clathrin / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000737:chemistry; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000737:chemistry*; D021962:Membrane Microdomains; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
D001713:Biphenyl Compounds; D002966:Clathrin; D011990:Receptors, Transferrin; D013450:Sulfones; C531943:ferristatin; D002784:Cholesterol; D007501:Iron; D034281:Dynamins