Down-regulation of a manganese transporter in the face of metal toxicity.
The yeast Smf1p Nramp manganese transporter is posttranslationally regulated by environmental manganese. Smf1p is stabilized at the cell surface with manganese starvation, but is largely degraded in the vacuole with physiological manganese through a mechanism involving the Rsp5p adaptor complex Bsd2p/Tre1p/Tre2p. We now describe an additional level of Smf1p regulation that occurs with toxicity from manganese, but not other essential metals. This regulation is largely Smf1p-specific. As with physiological manganese, toxic manganese triggers vacuolar degradation of Smf1p by trafficking through the multivesicular body. However, regulation by toxic manganese does not involve Bsd2p/Tre1p/Tre2p. Toxic manganese triggers both endocytosis of cell surface Smf1p and vacuolar targeting of intracellular Smf1p through the exocytic pathway. Notably, the kinetics of vacuolar targeting for Smf1p are relatively slow with toxic manganese and require prolonged exposures to the metal. Down-regulation of Smf1p by toxic manganese does not require transport activity of Smf1p, whereas such transport activity is needed for Smf1p regulation by manganese starvation. Furthermore, the responses to manganese starvation and manganese toxicity involve separate cellular compartments. We provide evidence that manganese starvation is sensed within the lumen of the secretory pathway, whereas manganese toxicity is sensed within an extra-Golgi/cytosolic compartment of the cell.
Department of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. ljensen@jhsph.edu
Laran T
LT
Jensen
Mark C
MC
Carroll
Matthew D
MD
Hall
Christopher J
CJ
Harvey
Sara E
SE
Beese
Valeria C
VC
Culotta
D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008345:Manganese / Q000172:deficiency / Q000378:metabolism / Q000633:toxicity*; D009154:Mutation / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
D027682:Cation Transport Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C105116:SMF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D008345:Manganese; D043743:Ubiquitin-Protein Ligase Complexes; C461959:TUL1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; C469287:RSP5 protein, S cerevisiae