Damage to newly synthesized proteins is a major cause of Cd(II) toxicity counteracted by proteasomes and integrated stress response in human cells.

Cadmium (Cd) is a biopersistent metal causing cancer and toxicity in several human tissues. Cd(II) lacks DNA binding or direct redox activity and its toxicity may result from protein damage. However, it is unclear what proteins are preferentially damaged by Cd(II) and whether global or protein-specific damage underlies its main pathologies. We examined the origin and toxicological significance of the global proteotoxic stress induced by Cd(II) in human lung and kidney cells, including primary renal proximal tubule cells. In all cells, low doses of Cd(II) induced proteolytic K48-polyubiquitination and insolubility (denaturation) of proteins. Ubiquitination-inactive cells showed hyperaccumulation of Cd-denatured proteins and transient suppression of ubiquitination or proteasome activity severely impaired cell viability at otherwise nontoxic doses of Cd. Inhibition of the ubiquitin-proteasome system after Cd(II) treatments was also detrimental to cell viability, indicating ongoing protein damage. Newly synthesized polypeptides were the main source of Cd(II)-denatured proteins and inhibition of translation prevented the formation of cytosolic aggresomes with amyloid-like structures. Short-lived transcription (p53, c-MYC) or antiapoptotic (MCL1) factors were especially sensitive to unfolding/denaturation by Cd(II). Activation of integrated stress response by Cd(II) increased cell survival and lowered the burden of structurally damaged proteins although to a lesser extent than proteasome activity. Our findings identified newly synthesized proteins as the major target of toxic damage by Cd(II) in kidney proximal tubule and other cells and revealed a high vulnerability of short-lived proteins. Ubiquitin-proteasome system was critically important for removal of damaged proteins and Cd(II) tolerance by human cells.