Mechanism of Endogenous Regulation of the Type I Interferon Response by Suppressor of IκB Kinase ϵ (SIKE), a Novel Substrate of TANK-binding Kinase 1 (TBK1)

Marion, James; Roberts, Charlotte F.; Call, R. Jason; Forbes, Jonathan; Nelson, Kristina; Bell, John; Bell, Jessica K.

doi:10.1074/jbc.m112.440859

Cited by 21 publications

(28 citation statements)

References 51 publications

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“…Previous studies have reported that SIKE could function as a substrate of TBK1 in in vitro kinetic analyses 18 . Thus, we further examined the potential influence of SIKE phosphorylation status on TBK1.…”

Section: Resultsmentioning

confidence: 99%

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Deng¹,

Wang²,

Ji³

et al. 2016

Nat Commun

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Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

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Section: Resultsmentioning

confidence: 99%

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Deng¹,

Wang²,

Ji³

et al. 2016

Nat Commun

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“…TBK1 and IKKε provided the strongest site‐specific mTOR S2159 phosphorylation. Indeed, the mTOR amino acid sequence surrounding S2159 fits consensus motifs found in defined TBK1 substrates (i.e., IRF3; IRF7; optineurin; suppressor of IKKε [SIKE]; Wild et al , ; Marion et al , ) and bears similarity to an IKKε consensus phosphorylation motif (Fig A; Peters et al , ; Hutti et al , ). At this time, the upstream mTOR T2164 kinase remains unknown.…”

Section: Resultsmentioning

confidence: 99%

The IKK‐related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists

et al. 2017

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The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogene-induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through site-specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGF-receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulus-selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knock-in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFN-β production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1-mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.

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“…IRF3 phosphorylation at residues Ser-385 and Ser-386 has previously been shown to control its dimerization (23)(24)(25) upon which IRF3 translocates to the nucleus (26), and controls transcriptional regulation of cell survival and proliferation (2,11). In addition to IRF3, several other substrates, i. e., namely cRel, Akt, RalB, SIKE, etc., have been identified that attribute to TBK1 function (7)(8)(9)(27)(28)(29)(30). TBK1 requires phosphorylation at Ser-172 within the kinase domain activation loop to be activated.…”

Section: Introductionmentioning

confidence: 99%

Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

Muvaffak¹,

Pan²,

Yan³

et al. 2014

Molecular Cancer Research

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TBK1 (TANK-binding kinase 1) is a noncanonical IkB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-kB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non-small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3 S386 ) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3 S386 levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3 S386 levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1 S172 ).Finally, TBK1 inhibitors dose-dependently inhibited pIRF3 S386 in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity.Implications: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity.

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Mechanism of Endogenous Regulation of the Type I Interferon Response by Suppressor of IκB Kinase ϵ (SIKE), a Novel Substrate of TANK-binding Kinase 1 (TBK1)

Cited by 21 publications

References 51 publications

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

The IKK‐related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists

Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

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