ABSTRACT
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2'3'-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity.
Subject(s)
Lipid Metabolism , Nucleotidyltransferases , Animals , Mice , Liver X Receptors/metabolism , Nucleotidyltransferases/metabolism , DNA , Nucleotides, Cyclic/metabolism , Immunity, InnateABSTRACT
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.
Subject(s)
Interferon Type I , Membrane Proteins , Membrane Proteins/genetics , Immunity, Innate , Signal Transduction , Cytokines , Interferon Type I/pharmacologyABSTRACT
Accumulating evidence implicates that herpes simplex virus type 1 (HSV-1) has been linked to the development and progression of Alzheimer's disease (AD). HSV-1 infection induces ß-amyloid (Aß) deposition in vitro and in vivo, but the effect and precise mechanism remain elusive. Here, we show that HSV-1 infection of the brains of transgenic 5xFAD mice resulted in accelerated Aß deposition, gliosis, and cognitive dysfunction. We demonstrate that HSV-1 infection induced the recruitment of microglia to the viral core to trigger microglial phagocytosis of HSV-GFP-positive neuronal cells. In addition, we reveal that the NLRP3 inflammasome pathway induced by HSV-1 infection played a crucial role in Aß deposition and the progression of AD caused by HSV-1 infection. Blockade of the NLRP3 inflammasome signaling reduces Aß deposition and alleviates cognitive decline in 5xFAD mice after HSV-1 infection. Our findings support the notion that HSV-1 infection is a key factor in the etiology of AD, demonstrating that NLRP3 inflammasome activation functions in the interface of HSV-1 infection and Aß deposition in AD.
Subject(s)
Alzheimer Disease , Disease Progression , Herpesvirus 1, Human , Mice, Transgenic , Microglia , NLR Family, Pyrin Domain-Containing 3 Protein , Phagocytosis , Signal Transduction , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/virology , Mice , Microglia/metabolism , Microglia/pathology , Microglia/virology , Signal Transduction/physiology , Humans , Herpes Simplex/pathology , Herpes Simplex/immunology , Herpes Simplex/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Disease Models, Animal , Presenilin-1/genetics , Presenilin-1/metabolismABSTRACT
Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D3 and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.
Subject(s)
Antiviral Restriction Factors , Cathelicidins , Immunity, Innate , Interferons , Antiviral Restriction Factors/immunology , Cathelicidins/immunology , Humans , Interferons/immunology , Membrane Proteins/metabolism , Nucleotides, CyclicABSTRACT
Micro/nano-topography (MNT) is an important variable affecting osseointegration of bone biomaterials, but the underlying mechanisms are not fully understood. We probed the role of a AMOT130/YAP pathway in osteoblastic differentiation of bone marrow mesenchymal stems cultured on titanium (Ti) carrying MNTs. Ti surfaces with two well-defined MNTs (TiO2 nanotubes of different diameters and wall thicknesses) were prepared by anodization. Rat BMSCs were cultured on flat Ti and Ti surfaces carrying MNTs, and cell behaviors (i.e., morphology, F-actin development, osteoblastic differentiation, YAP localization) were studied. Ti surfaces carrying MNTs increased F-actin formation, osteoblastic gene expression, and protein AMOT130 production in BMSCs (all vs. flat Ti), and the surface carrying larger nantubes was more effective, confirming osteoblastic differentiation induced by MNTs. Elevation of the AMOT130 level (by inhibiting its degradation) increased the osteoblastic gene expression, F-actin formation, and nuclear localization of YAP. These show that, AMOT130/YAP is an important pathway mediating the translation of MNT signals to BMSC osteoblastic commitment, likely via the cascade: AMOT130 promotion of F-actin formation, increased YAP nuclear import, and activation of osteoblastic gene expression.