Structural advances in sterol-sensing domain-containing proteins

Wu, Xuelan; Yan, Renhong; Cao, Pingping; Qian, Hui‐Fen; Yan, Nieng

doi:10.1016/j.tibs.2021.12.005

Cited by 14 publications

(15 citation statements)

References 101 publications

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“…In the presence of sterols (or unsaturated fatty acids in the case of SREBP-1 processing), full-length SREBPs associate with two integral membrane proteins – SREBP cleavage-activating protein (SCAP) and insulin-induced gene (INSIG) – in the ER. When the intracellular level of sterols or fatty acids is low, INSIG is released and SREBP-SCAP is transported to the Golgi apparatus, where the full-length SREBP precursors are cleaved by site-1 protease (S1P; also known as MBTPS1 in mammals) and site-2 protease (S2P; also known as MBTPS2 in mammals), resulting in the release of the N-terminal fragment with the bHLH-Zip DNA-binding domain ( Goldstein et al, 2002 ; Rawson, 2003 ; Wu et al, 2022 ). These N-terminal SREBP fragments enter the nucleus and stimulate the expression of SREBP target genes.…”

Section: Introductionmentioning

confidence: 99%

Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

Zhang

Liu

et al. 2022

Disease Models &Amp; Mechanisms

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Fine-tuning of lipogenic gene expression is important for the maintenance of long-term homeostasis of the intracellular lipids. The SREBP family of transcription factors are master regulators that control the transcription of lipogenic and cholesterogenic genes, but the mechanisms modulating SREBP-dependent transcription are still not fully understood. We previously reported that CDK8, a subunit of the transcription cofactor Mediator complex, phosphorylates SREBP at a conserved Thr residue. Here, using Drosophila as a model system, we show that the phosphodeficient SREBP proteins (dSREBP-Thr390Ala) are more stable and more potent in stimulating the expression of lipogenic genes and promoting lipogenesis in vivo than wild-type dSREBP. In addition, starvation blocks the effects of wild-type dSREBP-induced lipogenic gene transcription, while phosphodeficient dSREBP is resistant to this effect. Furthermore, our biochemical analyses have identified six highly conserved amino acid residues in the N-terminus disordered region of dSREBP that are required for its interactions with both CDK8 and the Med15 subunit of the small Mediator complex. These results support that the concerted actions of CDK8 and Med15 are essential for the tight regulation of SREBP-dependent transcription.

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Section: Introductionmentioning

confidence: 99%

Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

Zhang

Liu

et al. 2022

Disease Models &Amp; Mechanisms

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“…To extend these observations specifically to cholesterol homeostasis, we used the GeneTrek tool 29 to search for neurodevelopmental disorders (NDDs) associated with mutations in genes controlling cholesterol metabolism (89 genes, KEGG pathways hsa04979 and hsa00900; Table S1). We also searched for NDD-associated genes predicted to contain sterol-sensing domains (SSD) (13 genes, Table S1) 32, 33 , a membrane domain contained in proteins involved in cholesterol biosynthesis (e.g. HMG-CoA reductase and 7-dehydrocholesterol reductase enzymes), intracellular cholesterol transport (NPC1), and cholesterol efflux involved in cell signaling (Patched-1, PTCH1).…”

Section: Resultsmentioning

confidence: 99%

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Czernecki

Dixit

Riezman³

et al. 2022

Preprint

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Most nervous system disorders manifest through alterations in neuronal signaling based on abnormalities in neuronal excitability, synaptic transmission, and cell survival. However, such neuronal phenotypes are frequently accompanied or even caused by metabolic dysfunctions in neuronal or nonneuronal cells. The tight packing and highly heterogenous properties of neural, glial and vascular cell types pose significant challenges to dissecting metabolic aspects of brain disorders. Perturbed cholesterol homeostasis has recently emerged as key parameter associated with sub-sets of neurodevelopmental disorders. However, approaches for tracking and visualizing endogenous cholesterol distribution in the brain have limited capability of resolving cell type-specific differences. We here develop tools for genetically-encoded sensors that report on cholesterol distribution in the mouse brain with cellular resolution. We apply these probes to examine sub-cellular cholesterol accumulation in two genetic mouse models of neurodevelopmental disorders, Npc1 and Ptchd1 knock-out mice. While both genes encode proteins with sterol-sensing domains that have been implicated in cholesterol transport, we uncover highly selective and cell type-specific phenotypes in cholesterol homeostasis. The tools established in this work should facilitate probing sub-cellular cholesterol distribution in complex tissues like the mammalian brain and enable capturing cell type-specific alterations in cholesterol flow between cells in models of brain disorders.

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“…In addition to the SSD these SCPs also contain the Patched domain and three of them contain the NPC1_N domain. Many SCPs in other organisms have similar domain organizations ( 37 ), suggesting that SCPs are relatively conserved in different lineages. As such, PcSCPs like other SCPs, may play a role in sterol related networks.…”

Section: Discussionmentioning

confidence: 99%

“…Although biochemical evidences have long before demonstrated that the SSD domain can directly bind to sterols ( 24 ), the working mechanisms of SCPs remained elusive until 2016 when structure determinations were performed supported by single-particle cryo-electron microscopy ( 39 ). Based on the molecular basis of the interaction between SCPs and sterols, it was suggested that SCPs be divided into two classes: moderator proteins and transporter proteins ( 37 ). Our results indicate that PcSCPs are important for P. capsici to utilize exogenous sterols, but it is still not clear whether they act as sterol moderators or sterol transporters in this pathogen.…”

Section: Discussionmentioning

confidence: 99%

Sterol-Sensing Domain (SSD)-Containing Proteins in Sterol Auxotrophic Phytophthora capsici Mediate Sterol Signaling and Play a Role in Asexual Reproduction and Pathogenicity

et al. 2023

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Structural advances in sterol-sensing domain-containing proteins

Cited by 14 publications

References 101 publications

Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Sterol-Sensing Domain (SSD)-Containing Proteins in Sterol Auxotrophic Phytophthora capsici Mediate Sterol Signaling and Play a Role in Asexual Reproduction and Pathogenicity

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