TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation

Huh, Jin Young; Reilly, Shannon M.; Abu-Odeh, Mohammad; Murphy, Anne N.; Mahata, Sushil K.; Zhang, Jinyu; Cho, Yoori; Seo, Jong Bae; Hung, Chao‐Wei; Green, Courtney R.; Metallo, Christian M.; Saltiel, Alan R.

doi:10.1016/j.cmet.2020.10.010

Cited by 65 publications

(58 citation statements)

References 59 publications

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“…Intriguingly, ACSL1 localization at mitochondria appears to be regulated by TANK-Binding Kinase 1 in response to fasting. Relocalization of ACSL1 to mitochondria subsequently increases β-oxidation (Huh et al ., 2020). Similarly, the ER-LD tethering protein Snx14 interacts with ACSL4 (Datta et al ., 2020), an isoenzyme of which localizes to ER/LDs (Küch et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Miner

Edwards

et al. 2022

Preprint

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Cells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (Plin5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) trafficking and beta-oxidation during starvation of myoblasts requires both phosphorylation of Plin5 and an intact Plin5 mitochondrial tethering domain. We further identified the acyl-CoA synthetase, Fatp4 (ACSVL4) as a novel mitochondrial interactor of Plin5. The C-terminal domains of Plin5 and Fatp4 constitute a minimal protein interaction capable of inducing organelle contacts. Our work suggests that starvation leads to phosphorylation of Plin5, lipolysis, and subsequent channeling of FAs from LDs to Fatp4 on mitochondria for conversion to fatty-acyl-CoAs and subsequent oxidation.

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Section: Discussionmentioning

confidence: 99%

Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Miner

Edwards

et al. 2022

Preprint

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“…Recent studies have clearly established the causality of TBK1 in the pathogenesis of NAFLD (Reilly et al, 2013;Cruz et al, 2018;Huh et al, 2020) although the regulation of its expression and/or activity is not completely understood. Here we provide evidence to show that BRG1 plays dual roles in the regulation of FIGURE 2 | BRG1 interacts with AP-1 to activate TBK1 transcription.…”

Section: Discussionmentioning

confidence: 99%

“…TBK1 is an atypical kinase whose activity is primarily regulated by autophosphorylation although upstream priming kinases for TBK1 have also been reported (Ma et al, 2012). Mounting evidence suggests that TBK1 is a regulator of NAFLD pathogenesis by programming the innate immune response and by altering hepatic metabolism (Reilly et al, 2013;Cruz et al, 2018;Huh et al, 2020). However, it is not clear (1) whether or not BRG1 may influence TBK1 expression/activity and (2) whether TBK1 may regulate ROS production in the context of NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production

Shao

Xue

et al. 2021

Front. Cell Dev. Biol.

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Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte. Here we report that BRG1 deletion led to simultaneous down-regulation in expression and phosphorylation of tank binding kinase 1 (TBK1) in vivo and in vitro. On the one hand, BRG1 interacted with AP-1 to bind to the TBK1 promoter and directly activated TBK1 transcription in hepatocytes. On the other hand, BRG1 interacted with Sp1 to activate the transcription of c-SRC, a tyrosine kinase essential for TBK1 phosphorylation. Over-expression of c-SRC and TBK1 corrected the deficiency in ROS production in BRG1-null hepatocytes whereas depletion of TBK1 or c-SRC attenuated ROS production. In conclusion, our data suggest that dual regulation of TBK1 activity, at the transcription level and the post-transcriptional level, by BRG1 may constitute an important mechanism underlying excessive ROS production in hepatocytes.

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“…Beyond its well-known role in innate immunity, TBK1 has been implicated in oncogenesis and metabolic disorders linked to obesity such as type II diabetes, similar to mTOR and Akt (14)(15)(16)(17)28,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). In oncogenic KRas transformed cells, TBK1 promotes cell proliferation and survival and the growth of tumor explants in vivo, with either mTORC1 or Akt suggested as downstream mediators of TBK1 action (14)(15)(16)(17)(42)(43)(44)(45)(46).…”

Section: Introductionmentioning

confidence: 99%

The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt

Tooley

Kazyken

Bodur

et al. 2021

Preprint

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TBK1 (TANK-binding kinase 1) responds to microbial pathogens to initiate cellular responses critical for host innate immune defense. We found previously that TBK1 phosphorylates mTOR (mechanistic target of rapamycin) (on S2159) to increase mTOR complex 1 (mTORC1) activity and signaling in response to the growth factor EGF and the viral dsRNA mimetic poly(I:C). mTORC1 and the less well studied mTORC2 respond to diverse cues to control cellular metabolism, proliferation, and survival. Here we demonstrate that TBK1 activates mTOR complex 2 (mTORC2) directly to increase Akt phosphorylation at physiological levels of protein expression. We find that TBK1 phosphorylates mTOR S2159 within mTORC2 in vitro, phosphorylates mTOR S2159 in cells, and interacts with mTORC2 in cells. By studying MEFs lacking TBK1, as well as MEFs, macrophages, and mice bearing an Mtor S2159A knock-in allele (MtorA/A), we show that TBK1 and mTOR S2159 phosphorylation increase mTORC2 catalytic activity and promote mTOR-dependent downstream signaling to Akt in response to several growth factors and poly(I:C). While microbial-derived stimuli activate TBK1, we find that growth factors fail to activate TBK1 or increase mTOR S2159 phosphorylation in MEFs. Thus, we propose that basal TBK1 activity cooperates with growth factors in parallel to increase mTORC2 (and mTORC1) signaling. Collectively, these results reveal crosstalk between TBK1 and mTOR complexes (mTORCs), key nodes within two major signaling systems. As TBK1 and mTORCs have each been linked to tumorigenesis and metabolic disorders, these kinases may work together in a direct manner in a variety of physiological and pathological settings.

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TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation

Cited by 65 publications

References 59 publications

Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport

Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production

The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt

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