S6K-STING interaction regulates cytosolic DNA–mediated activation of the transcription factor IRF3

Wang, Fuan; Alain, Tommy; Szretter, Kristy J.; Stephenson, Kyle B.; Pol, Jonathan; Atherton, Matthew J.; Hoang, Huy-Dung; Fonseca, Bruno D.; Zakaria, Chadi; Chen, Lan; Rangwala, Zainab; Hesch, Adam; Chan, Eva Sin Yan; Tuinman, Carly; Suthar, Mehul S.; Jiang, Zhaozhao; Ashkar, Ali A.; Thomas, George; Kozma, Sara C.; Gale, Michael; Fitzgerald, Katherine A.; Diamond, Michael S.; Mossman, Karen; Sonenberg, Nahum; Wan, Yonghong; Lichty, Brian D.

doi:10.1038/ni.3433

Cited by 69 publications

(68 citation statements)

References 50 publications

(113 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, TBK1 adaptors Nap1 ( AZI2 ), Sintbad ( TBKBP1 ), or TANK all displayed dissimilar subcellular localization in a study of TBK1 network engagement (51). While our work, and related observations, suggest the TBK1/S6K regulatory relationship can support survival of some cancer cell types, these observations may also have important mechanistic implications for S6K-dependent innate immune signaling within the STING-TBK1 pathway (48). …”

Section: Discussionmentioning

confidence: 50%

“…For example, TBK1 is recruited by TRAF-mediated ubiquitination of MAVS or TRIF to mediate innate immune responses to viral RNA-sensing by RIG-1 or bacterial LPS-sensing by TLR4, respectively (44). Furthermore TBK1 is directly engaged in response to cytosolic DNA-sensing by its association with S6K/STING complexes downstream of cGAS (44,48). Within these stimuli-specific complexes, TBK1 phosphorylates adaptor proteins to recruit IRF3 for subsequent phosphorylation by TBK1, allowing IRF3 homodimerization and translocation to the nucleus to induce type I interferons (44).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer

Cooper

McMillan

et al. 2017

Cancer Research

View full text Add to dashboard Cite

Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiological contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely dependent on TBK1-mediated support of AKT/mTORC1 pathway activation for survival.

show abstract

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer

Cooper

McMillan

et al. 2017

Cancer Research

View full text Add to dashboard Cite

show abstract

“…These molecular findings establish a plausible mechanism by which chronic STING activation and trafficking not only recruit TBK1 for IRF3 signaling but also bring TBK1 to close proximity with mTORC1 on the lysosomes. Consistent with this finding, mTORC1 substrate S6K was recently shown to be recruited to the STING-TBK1 complex to promote IFN signaling during acute DNA stimulation (23). The molecular details of the interaction between the STING signalsome and the mTORC1 complex, as well as functional consequences during acute and chronic DNA stimulation, require further investigation.…”

Section: Chronic Inflammation Dysregulated Metabolismmentioning

confidence: 57%

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.

View full text Add to dashboard Cite

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...

show abstract

“…Immunoprecipitation analysis also did not reveal evidence of ALK binding to other recently identified cytosolic STING-interacting partners such as TIR [Toll/interleukin-1 (IL-1) receptor] domain–containing adapter-inducing IFNβ (TRIF) (30) or the ribosomal protein S6 kinase (fig. S5, A to C) (31). These findings suggest that ALK-mediated STING activation may not be dependent on direct binding to known cytosolic regulators of the STING pathway in macrophages and monocytes.…”

Section: Resultsmentioning

confidence: 99%

ALK is a therapeutic target for lethal sepsis

et al. 2017

View full text Add to dashboard Cite

Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)–mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.

show abstract

S6K-STING interaction regulates cytosolic DNA–mediated activation of the transcription factor IRF3

Cited by 69 publications

References 50 publications

TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer

TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer

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

ALK is a therapeutic target for lethal sepsis

Contact Info

Product

Resources

About