Macrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance

Yongli Qin; Lina Jia; Huijiao Liu; Wenqiang Ma; Xinmin Ren; Haifeng Li; Yuanwu Liu; Haiwen Li; Shuoqian Ma; Mei Liu; Pingping Li; Jinghua Yan; Jiyan Zhang; Yangdong Guo; Hua You; Yan Guo; Nafis A Rahman; Sławomir Wołczyński; Adam Kretowski; Dangsheng Li; Xiru Li; Fazheng Ren; Xiangdong Li

doi:10.1038/s41467-021-26408-3

Macrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance

Nat Commun. 2021 Oct 21;12(1):6121. doi: 10.1038/s41467-021-26408-3.

Authors

Yongli Qin^#¹, Lina Jia^#¹, Huijiao Liu^#¹, Wenqiang Ma^#¹, Xinmin Ren¹, Haifeng Li¹, Yuanwu Liu¹, Haiwen Li², Shuoqian Ma¹, Mei Liu³, Pingping Li⁴, Jinghua Yan⁵, Jiyan Zhang⁶, Yangdong Guo⁷, Hua You⁸, Yan Guo¹, Nafis A Rahman^{9

10}, Sławomir Wołczyński¹⁰, Adam Kretowski¹¹, Dangsheng Li¹², Xiru Li¹³, Fazheng Ren¹⁴, Xiangdong Li^{15

16}

Affiliations

¹ State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
² Agricultural Research Station, College of Agriculture, Virginia State University, Petersburg, VA, USA.
³ Department of Pathology, Chinese PLA General Hospital, Beijing, China.
⁴ Academy of Medical Sciences & Peking Union, Medical College, Beijing, China.
⁵ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
⁶ Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
⁷ State Key Laboratory of the Agro-Biotechnology, College of Horticultural Science, China Agricultural University, Beijing, China.
⁸ Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
⁹ Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
¹⁰ Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland.
¹¹ Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
¹² Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
¹³ Department of Surgery, Chinese PLA General Hospital, Beijing, China.
¹⁴ Department of Nutrition and Human Health, China Agricultural University, Beijing, China.
¹⁵ State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. xiangdongli@cau.edu.cn.
¹⁶ Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland. xiangdongli@cau.edu.cn.

^# Contributed equally.

Abstract

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / metabolism*
Animals
Disease Models, Animal
Endosomes / genetics
Endosomes / metabolism*
Female
Gene Deletion
Humans
Insulin Resistance*
Macrophages / metabolism*
Male
Mice
Mice, Knockout
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism*

Substances

Adaptor Proteins, Vesicular Transport
TICAM-1 protein, mouse
Toll-Like Receptor 4