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The role of RNF149 in the pre-emptive quality control substrate ubiquitination

ABSTRACT: Protein quality control is a continuous process in which a protein's folding status is constantly monitored. Mislocalized proteins (MLP), are processed by the various quality control pathways, as they are often misfolded due to inappropriate cellular surroundings. Polypeptides that fail to translocate into the ER due to an inefficient signal peptide, mutations or ER stress are recognized by the pre-emptive ER associated quality control (pEQC) pathway and degraded by the 26S proteasome. In this report we reveal the role of RNF149, a membrane bound E3 ligase in the ubiquitination of known pEQC substrates. We demonstrate its selective binding only to non-translocated proteins and its association with known pEQC components. Impairment in RNF149 function increases translocation flux into the ER and manifests in a myeloproliferative neoplasm (MPN) phenotype, a pathological condition associated with pEQC impairment. Finally, the dynamic localization of RNF149 may provides a molecular switch to regulate pEQC during ER stress. This project is lead by Ariel Stanhill (ariel.stanhill@gmail.com,Department of Natural and Life Sciences, The Open University of Israel, Raanana, Israel)

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Meital Kupervaser

LAB HEAD: Ami Navon

PROVIDER: PXD038478 | Pride | 2023-04-09

REPOSITORIES: Pride

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Project description:Background: Despite the established relation between energy restriction and metabolic health, the most beneficial nutrient composition of a weight-loss diet is still subject of debate. Objectives: The aim of the study was to examine the additional effects of nutrient quality on top of energy restriction(ER). Methods: A parallel-designed 12-week 25%ER dietary intervention study was conducted. Participants aged 40-70 years with abdominal obesity were randomized over three groups: a 25%ER high nutrient quality diet (n = 40); a 25%ER low nutrient quality diet (n = 40); or a habitual diet (n = 30). Both ER diets were nutritionally adequate, the high nutrient quality ER diet was enriched in monounsaturated and n-3 polyunsaturated fatty acids, fiber, and plant protein and reduced in fructose. Before and after the intervention intra-hepatic lipids, body fat distribution, fasting and postprandial responses to a mixed meal shake challenge test of cardio-metabolic risk factors, lipoproteins, vascular measurements, and adipose tissue transcriptome were assessed. Results: The high quality ER diet (-8.4 ± 3.2) induced 2.1 kg more weight loss (P = 0.007) than the low quality ER diet (-6.3 ± 3.9), reduced fasting serum total cholesterol (P = 0.014) and plasma triglycerides (P < 0.001), promoted an anti-atherogenic lipoprotein profile and induced a more pronounced decrease in adipose tissue gene expression of energy metabolism pathways than the low quality ER diet. Explorative analyses showed that the difference in weight loss between both ER diets were specifically present in insulin sensitive subjects (HOMA-IR ≤ 2.5), in whom the high nutrient quality diet induced 3.9 kg more weight loss than the low nutrient quality diet. Conclusion: A high nutrient quality 25%ER diet is more beneficial for cardiometabolic health than a low nutrient quality 25%ER diet. Overweight insulin sensitive subjects may benefit more from a high than a low nutrient quality ER diet with respect to weight loss, due to potential attenuation of glucose-induced lipid synthesis in adipose tissue. Trial registration: ClinicalTrials.gov NCT02194504.

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The role of RNF149 in the pre-emptive quality control substrate ubiquitination

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