Targeted Degradation of Glucose Transporters Protects against Arsenic Toxicity

Abstract

The abundance of cell surface glucose transporters must be precisely regulated to ensure optimal growth under constantly changing environmental conditions. We recently conducted a proteomic analysis of the cellular response to trivalent arsenic, a ubiquitous environmental toxin and carcinogen. A surprising finding was that a subset of glucose transporters was among the most downregulated proteins in the cell upon arsenic exposure. Here we show that this downregulation reflects targeted arsenic-dependent degradation of glucose transporters. Degradation occurs in the vacuole and requires the E2 ubiquitin ligase Ubc4, the E3 ubiquitin ligase Rsp5, and K63-linked ubiquitin chains. We used quantitative proteomic approaches to determine the ubiquitinated proteome after arsenic exposure, which helped us to identify the ubiquitination sites within these glucose transporters. A mutant lacking all seven major glucose transporters was highly resistant to arsenic, and expression of a degradation-resistant transporter restored arsenic sensitivity to this strain, suggesting that this pathway represents a protective cellular response. Previous work suggests that glucose transporters are major mediators of arsenic import, providing a potential rationale for this pathway. These results may have implications for the epidemiologic association between arsenic exposure and diabetes.

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

“…These data suggest that restricting cellular accumulation of this metalloid is an important means to protect the proteome from As(III)-induced damage and toxicity. The finding that cells respond to As(III) by downregulating arsenic influx pathways ( Jochem et al, 2019 ; Wysocki et al, 2001 ) and by increasing expression of arsenic export and sequestration systems ( Talemi et al, 2014 ; Thorsen et al, 2007 ) supports this notion. Besides arsenic influx and efflux, additional mechanisms to mitigate proteotoxicity exist; selected mutants affected in transcriptional and translational control had a clear impact on As(III)-induced protein aggregation and toxicity with intracellular arsenic levels comparable to wild-type cells ( …”

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity and an important role for transcriptional and translational control

“…Collectively, these data strongly suggest that intracellular arsenic is a direct cause of protein aggregation and that restricting the cellular accumulation of this metalloid is an important means for cells to protect their proteome from As(III)-induced damage and toxicity. Indeed, cells respond to As(III) by downregulating arsenic influx pathways [39,68] and by increasing expression of arsenic export and sequestration systems [48,69]. An important aspect of future work will be to systematically measure intracellular arsenic in all ~400 mutants identified in this study to pin-point pathways and regulators associated with arsenic uptake, efflux, intracellular distribution and sequestration.…”

Destabilization of Abnormal Methylation Enzymes: Nature’s Way to Eradicate Cancer Stem Cells

“…Arsenic trioxide is very toxic. It is also a potent carcinogen [41]. It is advisable to replace arsenic trioxide with the more effective and less toxic DHIs we have described [16,42].…”