Arsenite Binds to ZNF598 to Perturb Ribosome-Associated Protein Quality Control

Area of Science:

• Environmental Health
• Molecular Biology
• Cellular Stress Response

Background:

• Arsenic contamination in drinking water is a global health issue affecting millions.
• Protein misfolding and compromised protein quality control contribute to various human diseases.
• The molecular mechanisms of arsenic-induced proteotoxic stress are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which arsenic exposure induces proteotoxic stress in human cells.
• To investigate the interaction between arsenite and ZNF598 protein.
• To understand the role of ZNF598 in arsenic's effect on protein quality control.

Main Methods:

• Exposure of human skin fibroblasts to arsenite.
• Analysis of ubiquitination levels of RPS10 and RPS20.
• Assessment of poly(adenosine)-containing stalling sequence read-through.
• Comparison between wild-type and ZNF598 knockout cells.

Main Results:

• Arsenite exposure decreased ubiquitination of RPS10 (lysine 138/139) and RPS20 (lysine 8).
• These ubiquitination changes led to increased read-through of specific stalling sequences.
• The observed effects were dependent on ZNF598, as they were abolished in ZNF598 knockout cells.
• Arsenite was shown to directly interact with ZNF598 protein.

Conclusions:

• Arsenic exposure induces proteostatic stress through a novel mechanism involving ZNF598.
• Arsenite disrupts ribosome-associated protein quality control by altering RPS10 and RPS20 ubiquitination.
• ZNF598 plays a critical role in cellular defense against arsenic-induced proteotoxicity.