Yeast glutaredoxin, GRX4, functions as a glutathione S-transferase required for red ade pigment formation in Saccharomyces cerevisiae

As a tumor suppressor, p53 preserves genomic integrity in eukaryotes. However, limited evidence is availablefor the p53 shuttling between the cytoplasm and nucleus. Previous studies have shown that b-actin polymerization negatively regulates p53 nuclear import through its interaction with p53. In this study, we found thatDNA damage induces both b-actin and p53 accumulation in the nucleus. b-actin knockdown impaired thenuclear transport of p53. Additionally, b-actin could interact with p53 which was enhanced in response togenotoxic stress. Furthermore, N terminal deletion mutants of p53 shows reduced levels of association with bactin. We further identified Ser15, Thr18 and Ser20 of p53 are critical to the b-actin: p53 interaction, whichupon mutation into alanine abrogates the binding. Taken together, this study reveals that b-actin regulates thenuclear import of p53 through protein–protein interaction.

A futile cycle, formed between two ATP-dependant γ-glutamyl cycle enzymes, γ-glutamyl cysteine synthetase and 5-oxoprolinase: the cause of cellular ATP depletion in nephrotic cystinosis.

Cystinosis, an inherited disease caused by a defect in the lysosomal cystine transporter (CTNS), is characterized by renal proximal tubular dysfunction. Adenosine triphosphate (ATP) depletion appears to be a key event in the pathophysiology of the disease, even though the manner in which ATP depletion occurs is still a puzzle. We present a model that explains how a futile cycle that is generated between two ATP-utilizing enzymes of the γ-glutamyl cycle leads to ATP depletion. The enzyme γ-glutamyl cysteine synthetase (γ-GCS), in the absence of cysteine, forms 5- oxoproline (instead of the normal substrate, γ-glutamyl cysteine) and the 5-oxoproline is converted into glutamate by the ATP-dependant enzyme, 5-oxoprolinase. Thus, in cysteine-limiting conditions, glutamate is cycled back into glutamate via 5-oxoproline at the cost of two ATP molecules without production of glutathione and is the cause of the decreased levels of glutathione synthesis, as well as the ATP depletion observed in these cells. The model is also compatible with the differences seen in the human patients and the mouse model of cystinosis, where renal failure is not observed.