Casein Kinase 1 Regulates Sterol Regulatory Element-binding Protein (SREBP) to Control Sterol Homeostasis

Brookheart, Rita T.; Lee, Chih Yung S.; Espenshade, Peter J.

doi:10.1074/jbc.m113.511899

Cited by 10 publications

(9 citation statements)

References 66 publications

(72 reference statements)

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“…Sre1N degradation [13], we found that deletion of hhp2 + significantly increased SRE2 reporter activity in the presence/absence of CLZ, TER or CoCl 2 (Fig 4A-4C), thus further validating our reporter system. Surprisingly, in deletion of ssp2 + gene, encoding the AMP-activated protein kinase (AMPK) α Subunit, CLZ, TER or CoCl 2 -induced Sre1 activity was significantly suppressed (Fig 5A-5C).…”

Section: Deletion Of Ssp2 Or/and Gsk3/gsk31 Markedly Suppressed Clz supporting

confidence: 73%

“…Recent studies have shown that a highly conserved casein kinase 1 family member Hhp2 phosphorylates Sre1N and accelerates Sre1N degradation, but it seems like that Hhp2 is not the sole Sre1N kinase. Sre1N contains at least 22 phosphorylated serine and threonine residues [13], suggesting that additional kinases might be involved in Sre1 activity regulation.…”

Section: Introductionmentioning

confidence: 99%

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AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

et al. 2020

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Sterol regulatory element-binding protein (SREBP), a highly conserved family of membrane-bound transcription factors, is an essential regulator for cellular cholesterol and lipid homeostasis in mammalian cells. Sre1, the homolog of SREBP in the fission yeast Schizosaccharomyces pombe (S. pombe), regulates genes involved in the transcriptional responses to low sterol as well as low oxygen. Previous study reported that casein kinase 1 family member Hhp2 phosphorylated the Sre1 N-terminal transcriptional factor domain (Sre1N) and accelerated Sre1N degradation, and other kinases might exist for regulating the Sre1 function. To gain insight into the mechanisms underlying the Sre1 activity and to identify additional kinases involved in regulation of Sre1 function, we developed a luciferase reporter system to monitor the Sre1 activity through its binding site called SRE2 in living yeast cells. Here we showed that both ergosterol biosynthesis inhibitors and hypoxia-mimic CoCl 2 caused a dose-dependent increase in the Sre1 transcription activity, concurrently, these induced transcription activities were almost abolished in Δsre1 cells. Surprisingly, either AMPKα Subunit Ssp2 deletion or Glycogen Synthase Kinases Gsk3/Gsk31 double deletion significantly suppressed ergosterol biosynthesis inhibitors-or CoCl 2-induced Sre1 activity. Notably, the Δssp2Δgsk3Δgsk31 mutant showed further decreased Sre1 activity when compared with their single or double deletion. Consistently, the Δssp2Δgsk3Δgsk31 mutant showed more marked temperature sensitivity than any of their single or double deletion. Moreover, the fluorescence of GFP-Sre1N localized at the nucleus in wild-type cells, but significantly weaker nuclear fluorescence of GFP-Sre1N was observed in Δssp2, Δgsk3Δgsk31, Δssp2Δgsk3, Δssp2Δgsk31 or Δssp2Δgsk3Δgsk31 cells. On the other hand, the immunoblot showed a dramatic decrease in GST-Sre1N levels in the Δgsk3Δgsk31 or the Δssp2Δgsk3Δgsk31 cells but not in the Δssp2 cells. Altogether, our findings suggest that Gsk3/Gsk31 may regulate Sre1N degradation, while Ssp2 may regulate not only the degradation of Sre1N but also its translocation to the nucleus.

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Section: Deletion Of Ssp2 Or/and Gsk3/gsk31 Markedly Suppressed Clz supporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

et al. 2020

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“…CKI plays important roles in regulating several metabolic pathways through phosphorylation of the key regulators peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and N-terminal transcription factor domain of Sre1 (Sre1N), a yeast homolog of active SREBP, for proteasome dependent degradation (57, 58). In addition, CKIδ-mediated phosphorylation of hypoxia-inducible factor 1α (HIF-1α) suppresses HIF-1α-dependent LPIN1 mRNA expression, leading to a decrease in lipid synthesis under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

The SCF ^β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis

et al. 2017

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The SCFβ-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of β-transducin repeat-containing protein (β-TRCP) substrates is therefore critical to understand SCFβ-TRCP biology and function. Here, we used a β-TRCP-phosphodegron-motif specific antibody in a β-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple β-TRCP substrates. One of these substrates was Lipin1, an enzyme and suppressor of the family of sterol regulatory element-binding protein (SREBP) transcription factors, which activate genes encoding lipogenic factors. We showed that SCFβ-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in a manner that required phosphorylation of Lipin1 by mechanistic target of rapamycin 1 (mTORC1) and casein kinase I (CKI). β-TRCP depletion in HepG2 hepatocellular carcinoma cells resulted in increased Lipin1 protein abundance, suppression of SREBP-dependent gene expression, and attenuation of triglyceride synthesis. Moreover, β-TRCP1 knockout mice showed increased Lipin1 protein abundance and were protected from hepatic steatosis induced by a high-fat diet. Together, these data reveal a critical physiological function of β-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.

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“…CKI belongs to serine/threonine protein kinase family and is highly conserved in eukaryotes, mainly distributed in the cytoplasm, nucleus, cell membrane, and cytoskeleton (Graves and Roach 1995;Knippschild et al 2005). CKI isoforms participate in many cellular processes, such as DNA repair, metabolic regulation, control regulation of signal transduction, vesicular trafficking, cell cycle progression, and cell development (Brookheart et al 2014;Choksi et al 2014;Gorietti et al 2014). However, there is no detailed information about the CKI of S. erinacei.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of a Spirometra erinacei casein kinase I

et al. 2015

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The Spirometra erinacei casein kinase I (SeCKI) gene was cloned and expressed in Escherichia coli, and its characteristics were investigated in this study. The recombinant SeCP protein (rSeCKI) was purified. The vaccination of mice with rSeCKI induced the Th1/Th2-mixed type of immune response with Th2 predominant (high levels of IgG1). Western blotting analysis showed that rSeCP was recognized by the sera of plerocercoid-infected mice, and anti-rSeCP serum recognized the native SeCP protein of plerocercoid crude antigens. Transcription and expression of SeCP was observed at the plerocercoid and adult stages of S. erinacei. Immunolocalization identified SeCKI in the tegument and parenchymal tissues of plerocercoids and in the teguments of adults. SeCKI appeared to be essential indispensable for the S. erinacei development and survival in host, but its biological functions need to be further investigated.

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Casein Kinase 1 Regulates Sterol Regulatory Element-binding Protein (SREBP) to Control Sterol Homeostasis

Cited by 10 publications

References 66 publications

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

The SCF ^β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis

Molecular cloning and characterization of a Spirometra erinacei casein kinase I

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Casein Kinase 1 Regulates Sterol Regulatory Element-binding Protein (SREBP) to Control Sterol Homeostasis

Cited by 10 publications

References 66 publications

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast

The SCF β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis

Molecular cloning and characterization of a Spirometra erinacei casein kinase I

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Product

Resources

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The SCF ^β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis