Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses

Cell Metab. 2022 Jul 5;34(7):1023-1041.e8. doi: 10.1016/j.cmet.2022.05.005.

Na Zhou ¹, Hailong Qi ², Junjun Liu ³, Guangze Zhang ⁴, Jianping Liu ⁵, Ning Liu ⁴, Minglu Zhu ⁴, Xuyang Zhao ⁴, Chang Song ⁴, Zhe Zhou ⁴, Jingjing Gong ⁴, Ridong Li ⁴, Xinyu Bai ⁴, Yan Jin ⁴, Yongfeng Song ⁶, Yuxin Yin ⁷

Affiliations

1 Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
2 Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China.
3 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University, Jinan, Shandong 250021, China.
4 Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
5 Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
6 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University, Jinan, Shandong 250021, China; Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China. Electronic address: [email protected].
7 Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China; Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China. Electronic address: [email protected].

PMID: 35675826 DOI: 10.1016/j.cmet.2022.05.005

Abstract

The ovarian-tumor-domain-containing deubiquitinases (OTUDs) block ubiquitin-dependent protein degradation and are involved in diverse signaling pathways. We discovered a rare OTUD3 c.863G>A mutation in a family with an early age of onset of diabetes. This mutation reduces the stability and catalytic activity of OTUD3. We next constructed an experiment with Otud3^-/- mice and found that they developed worse obesity, dyslipidemia, and Insulin resistance than wild-type mice when challenged with a high-fat diet (HFD). We further found that glucose and fatty acids stimulate CREB-binding-protein-dependent OTUD3 acetylation, promoting its nuclear translocation, where OTUD3 regulates various genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing peroxisome-proliferator-activated receptor delta (PPARδ). Moreover, targeting PPARδ using a specific agonist can partially rescue the phenotype of HFD-fed Otud3^-/- mice. We propose that OTUD3 is an important regulator of energy metabolism and that the OTUD3 c.863G>A is associated with obesity and a higher risk of diabetes.

Keywords

OTUD3; PPARδ; acetylation; metabolic homeostasis; nuclear translocation.

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