STING Exerts Antiviral Innate Immune Response by Activating Pentose Phosphate Pathway

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 Dec 19

PMID 39695767

Authors

Dan-Hui Wu

Zi-Long Zhao

Wei-Tao Yin

Huai Liu

Xiong-Yan Xiang

Ling-Jun Zhu

Jun-Qi Li

Zhen-Hua Yan

Yu-Jia Li

Yong-Ping Jian

Zhi-Xiang Xu

Affiliations

Soon will be listed here.

Abstract

Background: The innate immune system serves as the host's first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.

Methods: Metabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.

Results: In this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.

Conclusion: Our findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.

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