Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation

Yu, Jiayi; Zhou, Xiaofei; Chang, Mikyoung; Nakaya, Masato; Chang, Jae Hoon; Xiao, Yichuan; Lindsey, J. W.; Dorta‐Estremera, Stephanie; Cao, Wei; Zal, Anna; Żal, Tomasz; Sun, Shao Cong

doi:10.1038/ncomms7074

Cited by 89 publications

(95 citation statements)

References 52 publications

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“…TBK1 has been shown to inhibit mTORC1 activity in prostate cancer cells (12,20). T cell-specific ablation of TBK1 also enhances mTORC1 signaling in an experimental autoimmune encephalomyelitis model (20). We recently showed that pharmacological inhibition of TBK1 ameliorates disease phenotypes in Trex1 −/− mice (21).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its role in innate immunity, TBK1 also plays an important role in cell proliferation and cancer (19), and Tbk1 deficiency is embryonic-lethal. TBK1 has been shown to inhibit mTORC1 activity in prostate cancer cells (12,20). T cell-specific ablation of TBK1 also enhances mTORC1 signaling in an experimental autoimmune encephalomyelitis model (20).…”

Section: Discussionmentioning

confidence: 99%

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Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Three-prime repair exonuclease 1 knockout (Trex1 −/− ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANKbinding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 −/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 −/− background, and many metabolic defects persist in Trex1 −/− Irf3 −/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 −/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 −/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.M ammals have evolved complex and integrated systems of immunity and metabolism to maintain and defend internal and environmental threats. Increasing numbers of immune regulators have been found to play critical roles in metabolism. Studies from recent years have established an integrated view on the shared architecture between adaptive immunity and metabolism, including how they correspond to stimulus in disease settings. However, cell-intrinsic innate immune regulation of metabolic pathways remains poorly understood. This is in part due to the fact that overwhelming systemic inflammation in chronic diseases often masks direct underlying molecular causes.We have previously characterized an autoimmune/autoinflammatory disease mouse model, three-prime repair exonuclease 1 knockout (Trex1 −/− ) (1). TREX1, also known as DNase III, is an exonuclease that localizes to the endoplasmic reticulum (ER) to prevent aberrant accumulation of self-DNA or glycans that would trigger immune activation (2, 3). Mutations of the TREX1 gene have been associated with several autoinflammatory and autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) (4). Trex1 −/− mice suffer from systemic inflammation caused largely by chronic activation of the cytosolic DNA sensing pathway through the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) cascade (5-7). We showed previously that TREX1 also regulates lysosomal biogenesis through the mTORC1-TFEB pathway and that Trex1 −/− mouse embryonic fibroblasts (MEFs) exhibit drastically reduced mTORC1 activity compare...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…TBK1 is involved in regulating rheumatoid synovitis by controlling TLR3-mediated activation of IRF7 and subsequent transcription of the IP-10 gene, which is closely related to the pathogenesis of rheumatoid arthritis [25]. TBK1 also acts as a key regulator in neuroinflammation, microvascular inflammation and gastritis [26][27][28]. Interestingly, TBK1 contributes to obesity regulation through the repression of energy expenditure.…”

Section: Potential Clinical Applications Of Tbk1 Inhibitorsmentioning

confidence: 97%

TBK1 inhibitors: a review of patent literature (2011 – 2014)

Yang

Yin

et al. 2015

Expert Opinion on Therapeutic Patents

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The role of TBK1 in various diseases has prompted the further investigation of significant targets. Although research on TBK1 inhibitors has increased over the last few years, only a few inhibitors of this kinase have been identified. In addition, almost all of the chemical inhibitors are modified from different scaffolds and/or chemotypes of pyrimidine. Specifically, compound BX795 is the representative one, which was first patented as a potent TBK1 inhibitor. Even though some compounds have displayed interesting potential inhibition and selectivity of TBK1 in vitro and in in vivo trials, the development of more efficient and selective TBK1 inhibitors is still required.

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“…Neutralization of TBK1 function leads to a phenotype very similar to C9orf72 neutralization. For instance, Cre-mediated removal of Tbk1 in T cells causes T cell activation and T cell infiltration of spleen and lymph nodes (16). Also, mice lacking TBK1 activity develop immune cell infiltrates in many organs and tissues, including skin, lung, liver and kidneys, and increased susceptibility to LPS-induced mortality (17).…”

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confidence: 99%