Resistance to cadmium mediated by ubiquitin-dependent proteolysis

Abstract

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.

The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

“…In addition, we found that VCP plays a critical role in Cd 2+ -induced aggresome formation. The potential for Cd 2+ to induce aggresome formation is supported by the observations that Cd 2+ causes broad protein misfolding and ubiquitination (Jungmann et al, 1993;Nies, 1999;Hall, 2002). Cd 2+ induces protein misfolding mainly through ion substitution and oxidation.…”

“…Cd 2+ also causes oxidative stress by promoting the formation of free radicals and depleting glutathione, and by binding to sulfhydryl groups of the proteins (Hall, 2002). In addition, Cd 2+ treatment has been shown to enhance the level of ubiquitinated proteins in mammalian and yeast cells (Jungmann et al, 1993;Figueiredo-Pereira and Cohen, 1999) through suppressing both ATP-dependent and -independent protein degradation, but not the protease activities of the 20S proteasome (Figueiredo-Pereira and Cohen, 1999). However, the mechanisms by which Cd 2+ inhibits protein degradation remain to be elucidated.…”

Characterization of functionally independent domains in the human ubiquitin conjugating enzyme UbcH2

“…heat shock and cadmium resistance [4,5] and peroxisome bk~genesis [6]. ~ttachment of the highly conserved protein ubiquitin to otl~er eukaryotic proteins targets them for selective degradatioa.…”

Identification and characterization of an activated 20S proteasome in Trypanosoma brucei

“…the cyclins) [4,11], transcriptional regulators (e.g. IKB and NF-KB) [7], as well as the abnormal proteins [12], which may arise from mutation or posttranslational damage. In most cases, the ATP-dependent proteolytic pathway is ubiquitin-dependent.…”