A New System for the Regulation of Glucose and Lipid Metabolism Found
Diabetes affects more than 400 million people worldwide and is a huge public health burden. Obesity is a major risk factor for diabetes and leads to insulin resistance that often precedes diabetes. Currently, genome-wide association studies (GWAS) have identified more than 80 diabetes susceptibility loci, and an increasing number of mutations and variants have been identified in monogenic forms of diabetes, such as young adult-onset diabetes (MODY). Determining the genetic factors of diabetes can help improve the understanding of the etiology and pathogenesis of this disease, and can provide strong support for early prevention and symptomatic intervention.
The ubiquitin-proteasome-dependent protein degradation process is the main pathway for regulating intracellular protein levels. This process is regulated by ubiquitin ligase-mediated ubiquitination of substrate proteins and deubiquitinase-mediated deubiquitination of substrate proteins. The ubiquitination and deubiquitination processes of proteins constitute the dynamics of protein metabolism balance. There are more than 1,000 ubiquitin ligases identified so far, but only more than 100 deubiquitinases, suggesting that each deubiquitinase has a broad spectrum of substrates and participates in a variety of life processes. In previous studies, it has been reported that deubiquitinase OTU family proteins play a key role in tumor cell apoptosis and drug resistance, but its role in energy metabolism remains unclear.
Recently, Tsinghua University-Peking University Joint Center for Life Sciences, Peking University Professor Yin Yuxin's team, and Shandong First Medical University Affiliated Provincial Hospital Professor Song Yongfeng's team jointly published a paper entitled Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional nutrition in Cell Metabolism. It revealed a novel mechanism by which the deubiquitinosomal system senses metabolic signals such as glucose and fatty acids and regulates energy metabolism. This study elaborates the process of deubiquitinase OTUD3 dynamically transmitting metabolic signals such as glucose/fatty acids into the nucleus and maintaining energy metabolism homeostasis, and its research results can provide directional guidance for the study of the pathogenesis of obesity and diabetes and provide a theoretical basis for the development of effective preventive and therapeutic measures.
The team found a diabetic family with features similar to juvenile-onset adult-onset diabetes (MODY), but genome whole exome sequencing did not detect causative gene mutations known to be associated with MODY, suggesting that the family may be caused by new causative genes. Further studies revealed that diabetic patients in this family carried the OTUD3 c.863G > A mutation, which encodes a protein OTUD3 that is a member of the OTU deubiquitinase family.
Experimental studies revealed that the OTUD3 c.863G > A mutation can substantially reduce the deubiquitinase activity as well as the protein's own stability of OTUD3. To prove whether the gene is associated with the pathogenesis of MODY hereditary diabetes, the team constructed Otud3 knockout mice and showed that Otud3 knockout mice developed early features of diabetes such as metabolic disorders and diet-induced obesity to form insulin resistance, indicating that loss of deubiquitinase function of OTUD3 causes obesity and increases the risk of diabetes. Further studies confirmed that OTUD3 can sense the energy status of the body and dynamically adjust the distribution in the cytoplasm and nucleus, which in turn maintains energy balance and thus inhibits obesity development. Mechanistic exploration showed that under glucose or fatty acid stimulation, acetyltransferase CBP senses acetyl-CoA produced by glycolipid metabolism to acetylate OTUD3, prompts OTUD3 to transport into the nucleus, excises the ubiquitin chains of a variety of transcription factors related to energy metabolism represented by PPARδ, slows down the degradation of these transcription factors, and prolongs their efficacy, in order to maintain the activity of cellular energy metabolism. However, when OTUD3 function appears impaired, the stability of a variety of transcription factors related to energy metabolism represented by PPARδ is reduced, making it difficult to maintain normal energy metabolism in cells, which in turn leads to obesity and diabetes. In addition, the team identified transcription factors that may be regulated by OTUD3 by CHIP-Seq combined with RNA-Seq experiments, validating that deubiquitinase regulates multiple substrates with similar functions and exerts strong functions. It also broadens the stability of classical deubiquitinase regulatory substrate proteins to the level of gene regulation.
In summary, this study discovered OTUD3, a new key pathogenic gene associated with the pathogenesis of obesity and diabetes, revealing a new regulatory mechanism of energy metabolism related to OTUD3 protein function, providing a new clue for finding potential therapeutic targets for obesity and diabetes.
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