Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity

• DOI: 10.1371/journal.ppat.1012048
• Publication Date: 2024-02-26T18:41:44Z
• Authors: Jing Han; Zhimeng Wang; Fangping Han; Bo Peng; Juanjuan Du; Conggang Zhang
• Keywords: Molecular Mechanisms of Inflammasome Activation and Regulation; Cell biology; QH301-705.5; Innate Immunity to Viral Infection; Immunology; Microtubule; FOS: Health sciences; Signal transduction; Interferon Signaling; Engineering; Biochemistry, Genetics and Molecular Biology; Health Sciences; Biology (General); Molecular Biology; Biology; Immunology and Microbiology; FOS: Clinical medicine; Innate immune system; Life Sciences; cGAS-STING Pathway; RC581-607; Immune Sensing; Innate Immunity; Sting; Infectious Diseases; Immune system; Aerospace engineering; Medicine; Interferon; Immunologic diseases. Allergy; Viral Hemorrhagic Fevers and Zoonotic Infections; Stimulator of interferon genes; Research Article

The activation of stimulator of interferon genes (STING) signaling induces the production of type I interferons (IFNs), which play critical roles in protective innate immunity for the host to defend against viral infections. Therefore, achieving sustained or enhanced STING activation could become an antiviral immune strategy with potential broad-spectrum activities. Here, we discovered that various clinically used microtubule-destabilizing agents (MDAs) for the treatment of cancer showed a synergistic effect with the activation of STING signaling in innate immune response. The combination of a STING agonist cGAMP and a microtubule depolymerizer MMAE boosted the activation of STING innate immune response and showed broad-spectrum antiviral activity against multiple families of viruses. Mechanistically, MMAE not only disrupted the microtubule network, but also switched the cGAMP-mediated STING trafficking pattern and changed the distribution of Golgi apparatus and STING puncta. The combination of cGAMP and MMAE promoted the oligomerization of STING and downstream signaling cascades. Importantly, the cGAMP plus MMAE treatment increased STING-mediated production of IFNs and other antiviral cytokines to inhibit viral propagation in vitro and in vivo. This study revealed a novel role of the microtubule destabilizer in antiviral immune responses and provides a previously unexploited strategy based on STING-induced innate antiviral immunity.