A Deubiquitylating Complex Required for Neosynthesis of a Yeast Mitochondrial ATP Synthase Subunit

The ubiquitin system is known to be involved in maintaining the integrity of mitochondria, but little is known about the role of deubiquitylating (DUB) enzymes in such functions. Budding yeast cells deleted for UBP13 and its close homolog UBP9 displayed a high incidence of petite colonies and slow respiratory growth at 37°C. Both Ubp9 and Ubp13 interacted directly with Duf1 (DUB-associated factor 1), a WD40 motif-containing protein. Duf1 activates the DUB activity of recombinant Ubp9 and Ubp13 in vitro and deletion of DUF1 resulted in the same respiratory phenotype as the deletion of both UBP9 and UBP13. We show that the mitochondrial defects of these mutants resulted from a strong decrease at 37°C in the de novo biosynthesis of Atp9, a membrane-bound component of ATP synthase encoded by mitochondrial DNA. The defect appears at the level of ATP9 mRNA translation, while its maturation remained unchanged in the mutants. This study describes a new role of the ubiquitin system in mitochondrial biogenesis

Comparison of waist-to-hip ratio and other obesity indices as predictors of cardiovascular disease risk in people with type-2 diabetes: a prospective cohort study from ADVANCE.

Item does not contain fulltextAIMS: The aim of this study was to compare the strength of associations and discrimination capability of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with cardiovascular disease risk in individuals with type-2 diabetes. METHODS AND RESULTS: Eleven thousand, one hundred and forty men and women were followed for a mean of 4.8 years. The Cox proportional hazard models were used to compute the hazard ratios and 95% confidence intervals (95% CI) for one standard deviation (SD) increase in baseline BMI (SD: 5 kg/m2), WC (SD: 13 cm) and WHR (SD: 0.08) with cardiovascular disease risk. After adjustment, hazard ratio (95% CI) for WC were 1.10 (1.03-1.18) for cardiovascular events, 1.13 (1.03-1.24) for coronary events, and 1.08 (0.98-1.19) for cardiovascular deaths. Estimates for WHR were 1.12 (1.05-1.19), 1.17 (1.08-1.28) and 1.19 (1.09-1.31). BMI was not related to any of these outcomes. Although the receiver operating characteristic curve could not differentiate between anthropometric variables (P values 0.24), the relative integrated discrimination improvement statistic showed an enhancement in the discrimination capabilities of models using WHR for cardiovascular outcomes, except for cerebrovascular events. CONCLUSION: Strengths of associations and discrimination statistics suggested that WHR was the best predictor of cardiovascular events and mortality in patients with type-2 diabetes and BMI the worst.1 april 201

Ear1p and Ssh4p Are New Adaptors of the Ubiquitin Ligase Rsp5p for Cargo Ubiquitylation and Sorting at Multivesicular Bodies

The ubiquitylation of membrane proteins destined for the vacuole/lysosome is essential for their recognition by the endosomal sorting machinery and their internalization into vesicles of multivesicular bodies (MVBs). In yeast, this process requires Rsp5p, an essential ubiquitin ligase of the Nedd4 family. We describe here two redundant proteins, Ear1p and Ssh4p, required for the vacuolar targeting of several cargoes originating from the Golgi or the plasma membrane. Ear1p is an endosomal protein that interacts with Rsp5p through its PPxY motifs, and it is required for the ubiquitylation of selected cargoes before their MVB sorting. In-frame fusion of cargo to ubiquitin overcomes the need for Ear1p/Ssh4p, confirming a role for these proteins in cargo ubiquitylation. Interestingly, Ear1p is itself ubiquitylated by Rsp5p and targeted to the vacuole. Finally, Ear1p overexpression leads to Rsp5p accumulation at endosomes, interfering with some of its functions in trafficking. Therefore, Ear1p/Ssh4p recruit Rsp5p and assist it in its function at MVBs by directing the ubiquitylation of specific cargoes