Resistance to cadmium mediated by ubiquitin-dependent proteolysis.
Cadmium is a potent poison for living cells. In man, chronic exposure to low levels of cadmium results in damage to kidneys and has been linked to neoplastic disease and ageing, and acute exposure can cause damage to a variety of organs and tissues. Cadmium reacts with thiol groups and can substitute for zinc in certain proteins, but the reason for its toxicity in vivo remains uncertain. In eukaryotes, an important selective proteolysis pathway for the elimination of abnormal proteins that are generated under normal or stress conditions is ATP-dependent and mediated by the ubiquitin system. Substrates of this pathway are first recognized by ubiquitin-conjugating enzymes (or auxiliary factors) which covalently attach ubiquitin, a small and highly conserved protein, to specific internal lysine residues of proteolytic substrates. Ubiquitinated substrates are then degraded by the proteasome, a multisubunit protease complex. Here we show that expression of this ubiquitin-dependent proteolysis pathway in yeast is activated in response to cadmium exposure and that mutants deficient in specific ubiquitin-conjugating enzymes are hypersensitive to cadmium. Moreover, mutants in the proteasome are hypersensitive to cadmium, suggesting that cadmium resistance is mediated in part by degradation of abnormal proteins. This indicates that a major reason for cadmium toxicity may be cadmium-induced formation of abnormal proteins.
Friedrich-Miescher-Laboratorium, Max-Planck-Gesellschaft, Tübingen, Germany.
J
J
Jungmann
H A
HA
Reins
C
C
Schobert
S
S
Jentsch
D000595:Amino Acid Sequence; D001483:Base Sequence; D002104:Cadmium / Q000494:pharmacology*; D003001:Cloning, Molecular; D003300:Copper / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000235:genetics; D005814:Genes, Viral; D007854:Lead / Q000494:pharmacology; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D017386:Sequence Homology, Amino Acid; D044763:Ubiquitin-Conjugating Enzymes; D014452:Ubiquitins / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
D014452:Ubiquitins; D002104:Cadmium; D007854:Lead; D003300:Copper; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases; D015032:Zinc