SCD1 licenses STING signaling through fatty acid desaturation–mediated membrane remodeling
Abstract
The stimulator of interferon genes (STING) is a critical mediator of innate immunity against cytosolic DNA pathogens, requiring precise regulation to balance antiviral defense and immune tolerance. While lipid metabolism influences immune signaling, the role of stearoyl-CoA desaturase 1 (SCD1), a key enzyme converting saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), in STING activation remains unexplored. Here, we identify SCD1 as a metabolic checkpoint that licenses STING activation through biophysical membrane remodeling. Mechanistically, SCD1-generated MUFAs incorporate into endoplasmic reticulum (ER) phospholipids, enhancing membrane curvature and fluidity. This biophysical remodeling facilitates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) binding to STING and promotes its dimerization, enabling downstream TBK1-IRF3 signaling and type I interferons (IFNs) production. Consequently, Scd1 deficiency or pharmacological inhibition impairs STING activation, attenuates antiviral responses against herpes simplex virus-1 (HSV-1), and exacerbates viral replication in vitro and in vivo. Conversely, MUFAs supplementation rescues STING activation in Scd1 -deficient models. Our findings establish SCD1-mediated lipid desaturation as a fundamental regulator of STING-driven immunity, highlighting its therapeutic potential for disorders of aberrant STING activation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Danhui Qin
Department of Pathogenic Biology, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Yanjie Gao
Department of Pathogenic Biology, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Haojia Jiang
Department of Pathogenic Biology, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Xintong Meng
Department of Pathogenic Biology, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Ying Qin
School of Chemical Engineering and Technology, Xi’an Jiaotong University
Hui Song
Advanced Catalytic Materials Research Center, School of Materials Science and Engineering
Yue Fu
Chengjiang Gao
Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Mutian Jia
Department of Pathogenic Biology, Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University
Chunyuan Zhao
State Key Laboratory for Innovation and Transformation of Luobing Theory, Department of Cardiology, Qilu Hospital of Shandong University
Wei Zhao