Yeast Npi3/Bro1 is involved in ubiquitin-dependent control of permease trafficking

FEBS Lett. 2002 Apr 24;517(1-3):103-9. doi: 10.1016/s0014-5793(02)02586-3.


The membrane traffic and stability of the general amino acid permease Gap1 of Saccharomyces cerevisiae are under nitrogen control. Addition of a preferential nitrogen source such as ammonium to cells growing on a poor nitrogen source induces internalization of the permease and its subsequent degradation in the vacuole. This down-regulation requires ubiquitination of Gap1 through a process involving ubiquitin ligase Npi1/Rsp5, ubiquitin hydrolase Npi2/Doa4, and Bul1/2, two Npi1/Rsp5 interacting proteins. Here we report that yet another protein, Npi3, is involved in the regulation of Gap1 trafficking. We show that Npi3 is required for NH4+-induced down-regulation of Gap1, and particularly for efficient ubiquitination of the permease. Npi3 plays a pleiotropic role in permease down-regulation, since it is also involved in ubiquitination and stress-induced down-regulation of the uracil permease Fur4 and in glucose-induced degradation of hexose transporters Hxt6/7. We further provide evidence that Npi3 is required for direct vacuolar sorting of neosynthesized Gap1 permease as it occurs in npr1 mutant cells. NPI3 is identical to BRO1, a gene encoding a protein of unknown biochemical function and recently proposed to be involved in protein turnover. Npi3/Bro1 homologues include fungal proteins required for proteolytic cleavage of zinc finger proteins and the mouse Aip1 protein involved in apoptosis. We propose that proteins of the Npi3/Bro1 family, including homologues from higher species, may play a conserved role in ubiquitin-dependent control of membrane protein trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cloning, Molecular
  • Conserved Sequence / genetics
  • Down-Regulation
  • Endosomes / metabolism
  • Eukaryotic Cells / metabolism
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Humans
  • Membrane Transport Proteins / metabolism*
  • Monosaccharide Transport Proteins / metabolism
  • Nucleotide Transport Proteins*
  • Protein Structure, Tertiary
  • Protein Transport / physiology
  • Saccharomyces cerevisiae Proteins / metabolism
  • Ubiquitin / metabolism*
  • Vacuoles / metabolism
  • Yeasts / metabolism*
  • alpha Karyopherins / chemistry
  • alpha Karyopherins / genetics
  • alpha Karyopherins / metabolism*


  • FUR4 protein, S cerevisiae
  • Fungal Proteins
  • HXT7 protein, S cerevisiae
  • Membrane Transport Proteins
  • Monosaccharide Transport Proteins
  • Nucleotide Transport Proteins
  • PALA protein, Emericella nidulans
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • alpha Karyopherins
  • karyopherin alpha 2