Biology subjects

Alimohammadi, F.

Publications and source records attributed to Alimohammadi, F..

3 recordsLinked to original sources

bioRxiv2024

Catabolism of extracellular glutathione supplies amino acids to support tumor growth

Restricting amino acids from tumors is an emerging therapeutic strategy with significant promise. While typically considered an intracellular antioxidant with tumor-promoting capabilities, glutathione (GSH) is a tripeptide of cysteine, glutamate, and glycine that can be catabolized, yielding amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here, we find that GSH catabolism promotes tumor growth. We show that depletion of intracellular GSH does not perturb tumor growth, and extracellular GSH is highly abundant in the tumor microenvironment, highlighting the potential importance of GSH outside of tumors. We find supplementation with GSH can rescue cancer cell survival and growth in cystine-deficient conditions, and this rescue is dependent on the catabolic activity of {gamma}-glutamyltransferases (GGTs). Finally, pharmacologic targeting of GGTs activity prevents the breakdown of circulating GSH, lowers tumor cysteine levels, and slows tumor growth. Our findings indicate a non-canonical role for GSH in supporting tumors by acting as a reservoir of amino acids. Depriving tumors of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Further, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.

cancer biology↗

bioRxiv2023

Proteome birthdating reveals age-selectivity of protein ubiquitination

Within a cell, proteins have distinct and highly variable half-lives. As a result, the molecular ages of proteins can range from seconds to years. How the age of a protein influences its environmental interactions is a largely unexplored area of biology. To investigate the age-selectivity of cellular pathways, we developed a methodology termed "proteome birthdating" that barcodes proteins based on their time of synthesis. We demonstrate that this approach provides accurate measurements of protein turnover kinetics without the requirement for multiple kinetic time points. As a first use case of the birthdated proteome, we investigated the age distribution of the human ubiquitinome. Our results indicate that the vast majority of ubiquitinated proteins in a cell consist of newly synthesized proteins and that these young proteins constitute the bulk of the degradative flux through the proteasome. Rapidly ubiquitinated nascent proteins are enriched in cytosolic subunits of large protein complexes. Conversely, proteins destined for the secretory pathway and vesicular transport have older ubiquitinated populations. Our data also identified a smaller subset of very old ubiquitinated cellular proteins that do not appear to be targeted to the proteasome for rapid degradation. Together, our data provide an age census of the human ubiquitinome and establish proteome birthdating as a robust methodology for investigating the protein age-selectivity of diverse cellular pathways. Significance StatementCellular proteins have widely different ages - whereas some have been recently synthesized, others have existed in the cell for days or even years. How a proteins age influences its functions and interactions is largely unknown because it is difficult to globally differentiate proteins based on their time of synthesis. To address this challenge, we developed an analytical method named "proteome birthdating" that can partition cellular proteins into multiple discernible age groups. As an example application, we used proteome birthdating to examine the protein age-selectivity of the ubiquitin proteasome system, a major protein degradation pathway in eukaryotes. Our results show that proteins destined for degradation by this pathway consist of either particularly young or particularly old proteins, with the former being the predominant population. Together, our results establish proteome birthdating as a useful approach for analyzing the turnover of proteins and investigating the functional consequences of their age.

biochemistry↗

bioRxiv2023

Glutathione supports lipid abundance in vivo

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the livers balance of redox buffering and triglyceride production.

biochemistry↗