Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

Minjun Liu^{1

2}, Kun Zhou³, Yang Sheng^{1

2}, Wen Zhang^{1

2}, Qiaoli Chen^{1

2}, Ziyue Chen^{1

2}, Xinyu Yang^{1

2}, Yuxin Jin^{1

2}, Fangtong Liu^{1

2}, Yinqiu Mu^{1

2}, Shu Su^{1

2}, Weikuan Feng^{1

2}, Ping Rong^{1

2}, Juan Wang⁴, Philip Cohen⁵, Hui Liang⁶, Tong-Jin Zhao⁴, Shuai Chen^{7

8

9}, Hong-Yu Wang^{10

11}

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
² MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
³ The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
⁴ State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai Qi Zhi Institute, Shanghai, 200438, China.
⁵ MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee Scotland, DD1 4HN, United Kingdom.
⁶ Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
⁷ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
⁸ MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
⁹ Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
¹⁰ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.
¹¹ MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.

PMID: 41136690
DOI: 10.1007/s11427-025-2957-9

Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

Minjun Liu et al. Sci China Life Sci. 2025.

. 2025 Oct 23.

doi: 10.1007/s11427-025-2957-9. Online ahead of print.

Authors

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
² MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
³ The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
⁴ State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai Qi Zhi Institute, Shanghai, 200438, China.
⁵ MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee Scotland, DD1 4HN, United Kingdom.
⁶ Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
⁷ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
⁸ MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
⁹ Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China. chenshuai@nju.edu.cn.
¹⁰ State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.
¹¹ MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.

PMID: 41136690
DOI: 10.1007/s11427-025-2957-9

Abstract

Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms. Inactivation of the insulin receptor (INSR) contributes to the development of insulin resistance, whose protein level is down-regulated in obesity through as yet-undefined mechanisms. Here we show that the E3-ligase TRAF6 is a critical regulator of INSR maturation, whose inactivation prevents palmitic acid- or high-fat diet-induced diminution of the INSR. Consequently, genetic inactivation of TRAF6 enhances insulin signaling that further increases muscle glucose uptake and inhibits hepatic gluconeogenesis. TRAF6 inactivation increases the proprotein convertase FURIN that controls the processing of pro-INSR to mature INSR. Mechanistically, TRAF6 associates with the Golgi apparatus, where it ubiquitinates the cytosolic tail of FURIN, leading to its lysosomal degradation. This TRAF6-FURIN axis also regulates cholesterol metabolism via PCSK9 processing in the circulation. Collectively, our results reveal a critical role of TRAF6 in regulating proprotein processing and have therapeutic implications for metabolic control.

Keywords: FURIN; TRAF6; insulin receptor; insulin sensitivity; proprotein processing; ubiquitination.

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Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest. Human studies were carried out with the study protocol (2018-SR-054) approved by the Ethics Committee of First Affiliated Hospital of Nanjing Medical University.

References

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Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

Affiliations

Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources

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