Cideb controls sterol‐regulated
            <scp>ER</scp>
            export of
            <scp>SREBP</scp>
            /
            <scp>SCAP</scp>
            by promoting cargo loading at
            <scp>ER</scp>
            exit sites

Su, Lü; Zhou, Linkang; Chen, Feng‐Jung; Wang, Huiming; Qian, Hui; Sheng, Yuan‐Yuan; Zhu, Yuangang; Yu, Hua; Gong, Xinqi; Li-hui, Cai; Yang, Xuerui; Xu, Li; Zhao, Tong‐Jin; Li, John; Chen, Xiaowei; Li, Peng

doi:10.15252/embj.2018100156

Cited by 37 publications

(18 citation statements)

References 72 publications

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“…Srebp forms are retained in the endoplasmic reticulum (ER) by a complex with the cholesterol sensor, Scap. This complex transfers to the Golgi for cleavage to the active nuclear form when cholesterol becomes depleted [90]. Srebp activation is also stimulated via the multi-protein mTORC1 complex, a sensor of metabolic homeostasis [76,91,92].…”

Section: A Systems Approach To Gvad-cyp1b1 Regulationmentioning

confidence: 99%

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development

et al. 2020

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Background Cytochrome P450 1b1 (Cyp1b1) deletion and dietary retinol deficiency during pregnancy (GVAD) affect perinatal liver functions regulated by Srebp. Cyp1b1 is not expressed in perinatal liver but appears in the E9.5 embryo, close to sites of retinoic acid (RA) signaling. Hypothesis Parallel effects of Cyp1b1 and retinol on postnatal Srebp derive from effects in the developing liver or systemic signaling. Approach Cluster postnatal increases in hepatic genes in relation to effects of GVAD or Cyp1b1 deletion. Sort expression changes in relation to genes regulated by Srebp1 and Srebp2.Test these treatments on embryos at E9.5, examining changes at the site of liver initiation. Use in situ hybridization to resolve effects on mRNA distributions of Aldh1a2 and Cyp26a1 (RA homeostasis); Hoxb1 and Pax6 (RA targets). Assess mice lacking Lrat and Rbp4 (DKO mice) that severely limits retinol supply to embryos. Results At birth, GVAD and Cyp1b1 deletion stimulate gene markers of hepatic stellate cell (HSC) activation but also suppress Hamp. These treatments then selectively prevent the postnatal onset of genes that synthesize cholesterol (Hmgcr, Sqle) and fatty acids (Fasn, Scd1), but also direct cholesterol transport (Ldlr, Pcsk9, Stard4) and retinoid synthesis (Aldh1a1, Rdh11). Extensive support by Cyp1b1 is implicated, but with distinct GVAD interventions for Srebp1 and Srebp2. At E9.5, Cyp1b1 is expressed in the septum transversum mesenchyme

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Section: A Systems Approach To Gvad-cyp1b1 Regulationmentioning

confidence: 99%

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development

et al. 2020

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“…SREBP is initially synthesized as a precursor protein with the N- and C-terminal ends facing the cytosol and two transmembrane segments spanning the endoplasmic reticulum (ER). Upon cholesterol depletion, SREBP and the associated SREBP-cleavage activating protein (SCAP), with the help of Cideb, rapidly translocate from the ER to the Golgi apparatus (Su et al, 2019 ). At the Golgi, SREBP is cleaved by site-1 protease (S1P) in the lumenal loop followed by a second cleavage by site-2 protease (S2P) within the membrane-spanning domain (Brown and Goldstein, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation

et al. 2020

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Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B’/B and C’/C. POST1 promotes the generation of the functional S1P-C’/C from S1P-B’/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.

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“…However, in response to ER stress, SREBPs overexpression increased the expression of cholesterolgenic and lipogenic gene, resulting in cholesterol and lipid accumulation and provoking consequent apoptosis. Three potential mechanisms by which ER stress induces SREBP activation: caspase-induced SREBP cleavage (Colgan, 2007), eIF2α-phosphorylation-dependent downregulation of INSIG (Birkenfeld et al, 2011) and GRP78 dissociation from the SCAP-SREBP complex (Su et al, 2019). Previous studies showed that in vitrooverexpression of GRP78 could decrease markers of ER stress, attenuate ER-stress-induced SREBP activation and lipid accumulation (Lhoták et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin alleviates the severity of rheumatoid arthritis via targeting UPR component GRP78

Zhang

Ge²,

Song

et al. 2021

Preprint

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Background and Purpose: Azithromycin (AZM) is a macrolide antibiotic with well-described anti-inflammatory properties. This study aimed to substantiate its treatment potential in rheumatoid arthritis (RA). Experimental Approach: Gene expression profiles were collected by RNA-sequencing and the effects of AZM were assessed in functional assays. In vitro and vivo assays for examining the blockade of glucose-regulated protein 78 (GRP78) actions by AZM: assays for defining the anti-inﬂammatory activity of AZM using fibroblast-like synoviocytes (FLSs) from RA patients as well as collagen-induced arthritis (CIA) in DBA/1 mice. Identification and characterization of the binding of AZM to GRP78 using drug affability responsive target stability assay, proteomics and cellular thermal shift assay. Detect AZM inhibition of GRP78 and dependence of AZM’s anti-arthritis activity on GRP78. Key Results: AZM reduced pro-inflammatory factor production, cell migration, invasion and chemo-attractive potential, enhanced apoptosis, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. AZM ameliorated the severity of CIA lesions. Transcriptional analyses implied that AZM treatment causes impairments in signaling cascades associated with cholesterol and lipid biosynthetic process. GRP78 was isolated as a novel target of AZM. AZM-mediated activation of unfolded protein response (UPR) via inhibiting GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (CHOP), but also for activation of sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic process. Further, deletion of GRP78 abolished AZM’s anti-arthritis activity. Conclusion and Implications: These findings confirmed that AZM is an anti-arthritis therapeutic drug for RA treatment.

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Cideb controls sterol‐regulated ER export of SREBP / SCAP by promoting cargo loading at ER exit sites

Cited by 37 publications

References 72 publications

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development

POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation

Azithromycin alleviates the severity of rheumatoid arthritis via targeting UPR component GRP78

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