TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Balka, Katherine R.; Louis, Cynthia; Saunders, Tahnee L.; Smith, Amber M.; Calleja, Dale J.; D'Silva, Damian B; Moghaddas, Fiona; Tailler, Maximilien; Lawlor, Kate E.; Zhan, Yifan; Burns, Christopher J.; Wicks, Ian P.; Miner, Jonathan J.; Kile, Benjamin T.; Masters, Seth L.; Nardo, Dominic De

doi:10.1016/j.celrep.2020.03.056

Cited by 299 publications

(264 citation statements)

References 79 publications

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“…Third generation lentiviral constructs including pSLIK-Neo (vector), hTDP-43 WT and Q331K were used to generate lentivirus as described ( Balka et al., 2020 ; Moghaddas et al., 2018 ). HEK293T cells were transiently transfected with pSLIK plasmids, pMDL (packaging), RSV-REV (packaging) and VSVg (envelope) using Lipofectamine 2000 diluted in OptiMEM (Thermo Fisher Scientific) to generate lentiviral particles.…”

Section: Methodsmentioning

confidence: 99%

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

Davidson

Harapas

et al. 2020

Cell

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Summary Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

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Section: Methodsmentioning

confidence: 99%

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

Davidson

Harapas

et al. 2020

Cell

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617

464

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“…Canonical NF-κB signaling deriving from cytokine receptors or TLR requires the use of TNF receptor-associated factor (TRAF)-6 or TRAF2 to activate the IκBα kinase (IKK) complex, which in turn phosphorylates IκBα and triggers its proteasomal degradation via the E3 ligase β-TrCP. STING responses require the IKK complex, which can be redundantly activated by TBK1 and its homolog IKKε in a manner that may involve the upstream kinase transforming growth factor-β-activated kinase 1 (TAK1) (76,77). NF-κB would usually be found as the p65/p50 (RelA/NF-κB1) heterodimer, the most common of NF-κB protein dimers (78).…”

Section: Overview Of Antiviral Cytosolic Dna Sensingmentioning

confidence: 99%

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

2020

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Cells express multiple molecules aimed at detecting incoming virus and infection. Recognition of virus infection leads to the production of cytokines, chemokines and restriction factors that limit virus replication and activate an adaptive immune response offering long-term protection. Recognition of cytosolic DNA has become a central immune sensing mechanism involved in infection, autoinflammation, and cancer immunotherapy. Vaccinia virus (VACV) is the prototypic member of the family Poxviridae and the vaccine used to eradicate smallpox. VACV harbors enormous potential as a vaccine vector and several attenuated strains are currently being developed against infectious diseases. In addition, VACV has emerged as a popular oncolytic agent due to its cytotoxic capacity even in hypoxic environments. As a poxvirus, VACV is an unusual virus that replicates its large DNA genome exclusively in the cytoplasm of infected cells. Despite producing large amounts of cytosolic DNA, VACV efficiently suppresses the subsequent innate immune response by deploying an arsenal of proteins with capacity to disable host antiviral signaling, some of which specifically target cytosolic DNA sensing pathways. Some of these strategies are conserved amongst orthopoxviruses, whereas others are seemingly unique to VACV. In this review we provide an overview of the VACV replicative cycle and discuss the recent advances on our understanding of how VACV induces and antagonizes innate immune activation via cytosolic DNA sensing pathways. The implications of these findings in the rational design of vaccines and oncolytics based on VACV are also discussed.

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“…In the process, STING is transported to the ERGIC, Golgi, and perinuclear regions, where it meets downstream factors, including protein kinase TBK1/IKKε, transcription factors IRF3 and NF-κB, and other cellular factors. Ultimately, IRF3 is phosphorylated by TBK1 and enters into the nucleus to induce IFN and cytokine production ( 4 , 81 – 84 ).…”

Section: The Structure and Subcellular Localization Of Stingmentioning

confidence: 99%

When STING Meets Viruses: Sensing, Trafficking and Response

Cai

Sun

et al. 2020

Front. Immunol.

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To effectively defend against microbial pathogens, the host cells mount antiviral innate immune responses by producing interferons (IFNs), and hundreds of IFN-stimulated genes (ISGs). Upon recognition of cytoplasmic viral or bacterial DNAs and abnormal endogenous DNAs, the DNA sensor cGAS synthesizes 2’,3’-cGAMP that induces STING (stimulator of interferon genes) undergoing conformational changes, cellular trafficking, and the activation of downstream factors. Therefore, STING plays a pivotal role in preventing microbial pathogen infection by sensing DNAs during pathogen invasion. This review is dedicated to the recent advances in the dynamic regulations of STING activation, intracellular trafficking, and post-translational modifications (PTMs) by the host and microbial proteins.

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TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Cited by 299 publications

References 79 publications

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

When STING Meets Viruses: Sensing, Trafficking and Response

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