Targeted Degradation of Glucose Transporters Protects against Arsenic Toxicity
| Autor: | Jessie Ang, Marta Isasa, John Hanna, Steven P. Gygi, Meera K. Bhanu, Marco Jochem, Helena M. Schnell, Lukas Ende, Yagmur Micoogullari, Angel Guerra-Moreno |
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| Rok vydání: | 2018 |
| Předmět: |
Proteomics
Glucose Transport Proteins Facilitative chemistry.chemical_element Down-Regulation Saccharomyces cerevisiae Protein degradation Arsenic 03 medical and health sciences 0302 clinical medicine Ubiquitin Downregulation and upregulation Molecular Biology 030304 developmental biology 0303 health sciences Microbial Viability biology Arsenic toxicity Glucose transporter Ubiquitination Transporter Cell Biology Ubiquitin ligase Biochemistry chemistry Mutation Proteolysis biology.protein 030217 neurology & neurosurgery Research Article |
| Zdroj: | Molecular and cellular biology. 39(10) |
| ISSN: | 1098-5549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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