TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation

Ou, Yi-Hung; Torres, Michael J.; Ram, Rosalyn; Formstecher, Étienne; Roland, Christina L.; Cheng, Tzuling; Brekken, Rolf A.; Wurz, Ryan P.; Tasker, Andrew S.; Polverino, Tony; Tan, Seng Lai; White, Michael A.

doi:10.1016/j.molcel.2011.01.019

Cited by 191 publications

(275 citation statements)

References 42 publications

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“…TBK1 is a member of the IκB kinase family and is ubiquitously expressed. 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).…”

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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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%

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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“…23 Given the capacity of IKK-related kinases TBK1 and IKKe to directly phosphorylate AKT, [24][25][26] we aimed to identify new TBK1 substrates through interactomic studies to better understand the molecular link between TBK1 and AKT. We conducted a yeast two-hybrid screen using the C-terminal domain of TBK1 (amino acids 529-729) fused to the DNA-binding domain of the GAL4 transcription factor as bait ( Figure 1a).…”

Section: Hpip Is a Tbk1-interacting Proteinmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...

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“…Besides acting as IRF3/7 kinases, TBK1 and IKK-i have been implicated in cell proliferation and oncogenesis (34,35). To investigate the contribution of TBK1 to GM-DC differentiation, we assessed the effect of human TBK1 overexpression in AZI2 -/-BM cells on the differentiation of GM-DCs.…”

Section: Azi2 Is Required For the Proliferation Of Gm-dcs Via Tbk1mentioning

confidence: 99%

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

Fukasaka

Ori

Kawagoe

et al. 2013

The Journal of Immunology

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TNFR-associated factor family member–associated NF-κB activator (TANK)–binding kinase 1 (TBK1) is critical for the activation of IFN regulatory factor 3 and type I IFN production upon virus infection. A set of TBK1-binding proteins, 5-azacytidine–induced gene 2 (AZI2; also known as NAP1), TANK, and TBK1-binding protein 1 (TBKBP1), have also been implicated in the production of type I IFNs. Among them, TANK was found to be dispensable for the responses against virus infection. However, physiological roles of AZI2 and TBKBP1 have yet to be clarified. In this study, we found that none of these TBK1-binding proteins is critical for type I IFN production in mice. In contrast, AZI2, but not TBKBP1, is critical for the differentiation of conventional dendritic cells (cDCs) from bone marrow cells in response to GM-CSF. AZI2 controls GM-CSF–induced cell cycling of bone marrow cells via TBK1. GM-CSF–derived DCs from AZI2-deficient mice show severe defects in cytokine production and T cell activation both in vitro and in vivo. Reciprocally, overexpression of AZI2 results in efficient generation of cDCs, and the cells show enhanced T cell activation in response to Ag stimulation. Taken together, AZI2 expression is critical for the generation of cDCs by GM-CSF and can potentially be used to increase the efficiency of immunization by cDCs.

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TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation

Cited by 191 publications

References 42 publications

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

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

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

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