1. Academic Validation
  2. Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages

Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages

  • Cell Rep. 2022 Nov 29;41(9):111738. doi: 10.1016/j.celrep.2022.111738.
Yingchun Wang 1 Yuzhen Wang 1 Lu Ding 1 Xiaolei Ren 1 Bo Wang 1 Liyuan Wang 1 Songbo Zhao 1 Xuetian Yue 2 Zhuanchang Wu 1 Chunyang Li 3 Xiaohong Liang 1 Chunhong Ma 1 Lifen Gao 4
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 2 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 3 Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 4 Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China. Electronic address: glfflg@sdu.edu.cn.
Abstract

Accumulating evidence indicates that macrophages reshape their Cholesterol metabolism in response to pathogens to support host defense. Intervention of host Cholesterol homeostasis has emerged as a promising strategy for Antiviral therapy. T cell immunoglobulin and Mucin domain-containing molecule 4 (Tim-4) is indispensable in maintaining the homeostasis of macrophages. However, its role in Antiviral innate immunity and Cholesterol metabolism remains unknown. Here, we report that Tim-4 deficiency results in boosted interferon (IFN) signaling and decreased viral load. Mechanistically, Tim-4 disturbs the Insig1-SCAP interaction and promotes SCAP-SREBP2 complex translocation to the Golgi apparatus, eventually leading to the upregulation of Cholesterol biosynthesis in macrophages, which limits the type I IFN response. Our findings demonstrate that Tim-4 suppresses type I IFN signaling by enhancing SREBP2 activation, delineating the role of Tim-4 in Antiviral innate immunity and Cholesterol metabolism, which sheds LIGHT on the mechanism by which Tim-4 orchestrates macrophage homeostasis.

Keywords

CP: Immunology; Insig1; SCAP; SREBP2; Tim-4; antiviral innate immune response; cholesterol metabolism.

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