cGAS suppresses β-cell proliferation by a STING-independent but CEBPβ-dependent mechanism

Zixin Cai; Yan Yang; Jiaxin Zhong; Yujiao Ji; Ting Li; Jing Luo; Shanbiao Hu; Hairong Luo; Yan Wu; Feng Liu; Jingjing Zhang

doi:10.1016/j.metabol.2024.155933

cGAS suppresses β-cell proliferation by a STING-independent but CEBPβ-dependent mechanism

Metabolism. 2024 May 8:155933. doi: 10.1016/j.metabol.2024.155933. Online ahead of print.

Authors

Zixin Cai¹, Yan Yang¹, Jiaxin Zhong¹, Yujiao Ji¹, Ting Li², Jing Luo², Shanbiao Hu³, Hairong Luo¹, Yan Wu¹, Feng Liu⁴, Jingjing Zhang⁵

Affiliations

¹ National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
² Departments of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
³ Departments of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
⁴ National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address: liuf001@csu.edu.cn.
⁵ National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address: Doctorzhangjj@csu.edu.cn.

PMID: 38729601
DOI: 10.1016/j.metabol.2024.155933

Abstract

Aims/hypothesis: cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes.

Methods: Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGAS^βKO) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing.

Results: cGAS expression is upregulated in the islets of diabetic mice and by high glucose treatment in MIN6 cells. Both global cGAS deficiency and β-cell-specific cGAS knockout mice lead to improved glucose tolerance by promoting β-cell mass. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS- but not STING-deficiency leads to reduced expression of CEBPβ, a known suppressor of β-cell proliferation, concurrently with increased β-cell proliferation. Moreover, overexpression of CEBPβ reverses the upregulation of Cyclin D1 and D2 induced by cGAS deficiency, thereby regulating β-cell proliferation. These results confirm that cGAS regulation of β-cell proliferation via a CEBPβ-dependent but STING-independent mechanism.

Conclusions/interpretation: Our findings highlight the pivotal role of cGAS in promoting β-cell proliferation and maintaining glucose homeostasis, potentially by regulating CEBPβ expression in a STING-independent manner. This study uncovers the significance of cGAS in controlling β-cell mass and identifies a potential therapeutic target for enhancing β-cell proliferation in the treatment of diabetes.

Keywords: CEBPβ; Diabetes; STING; cGAS; β-Cell proliferation.