Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2)

Biochemistry. 2006 Feb 21;45(7):2294-301. doi: 10.1021/bi052307m.

Abstract

The metal transporter DMT1 (Slc11a2) plays a vital role in iron metabolism. Alternative splicing of the 3' exon generates two DMT1 isoforms with different C-terminal protein sequences and a 3' untranslated region harboring (isoform I, +IRE) or not (isoform II, -IRE), an iron-responsive element. Isoform I is expressed at the plasma membrane of certain epithelial cells including the duodenum brush border, where it is essential for the absorption of nutritional iron. Isoform II is expressed in many cells and is essential for the acquisiton of transferrin iron from acidified endosomes. The targeting and trafficking properties of DMT1 isoforms I and II were studied in transfected LLC-PK(1) kidney cells, with respect to isoform-specific differences in function, subcellular localization, endocytosis kinetics, and fate upon internalization. Isoform I showed higher surface expression and was internalized from the plasma membrane with slower kinetics than that of isoform II. As opposed to isoform II, which is efficiently sorted to recycling endosomes upon internalization, isoform I was not efficiently recycled and was targeted to lysosomes. Thus, alternative splicing of DMT1 critically regulates the subcellular localization and site of Fe(2+) transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cation Transport Proteins / biosynthesis
  • Cation Transport Proteins / metabolism*
  • Endocytosis / physiology
  • Gene Expression
  • Iron-Binding Proteins / biosynthesis
  • Iron-Binding Proteins / metabolism*
  • LLC-PK1 Cells
  • Mice
  • Protein Isoforms / metabolism
  • Protein Transport
  • Swine

Substances

  • Cation Transport Proteins
  • Iron-Binding Proteins
  • Protein Isoforms
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2