title: Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter.
abstract: The Unfolded Protein Response (UPR) is an intracellular signaling pathway which is activated when unfolded or misfolded proteins accumulate in the Endoplasmic Reticulum (ER), a condition commonly referred to as ER stress. It has been shown that lipid biosynthesis is increased in ER-stressed cells. The N(ε)-lysine acetylation of ER-resident proteins, including chaperones and enzymes involved in the post-translational protein modification and folding, occurs upon UPR activation. In both ER proteins acetylation and lipid synthesis, acetyl-CoA is the donor of acetyl group and it is transported from the cytosol into the ER. The cytosolic pool of acetyl-CoA is mainly derived from the activity of mitochondrial citrate carrier (CiC). Here, we have demonstrated that expression of CiC is activated in human HepG2 and rat BRL-3A cells during tunicamycin-induced ER stress. This occurs through the involvement of an ER stress responsive region identified within the human and rat CiC proximal promoter. A functional Unfolded Protein Response Element (UPRE) confers responsiveness to the promoter activation by UPR transducers ATF6α and XBP1. Overall, our data demonstrate that CiC expression is activated during ER stress through the binding of ATF6α and XBP1 to an UPRE element located in the proximal promoter of Cic gene. The role of ER stress-mediated induction of CiC expression has been discussed.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy. Electronic address: fabrizio.damiano@unisalento.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Damiano
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Tocci
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy.
authors.forename: Gabriele Vincenzo
authors.initials: GV
authors.lastname: Gnoni
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Siculella
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019343:Citric Acid / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D056811:Unfolded Protein Response / Q000235:genetics*; D000071717:X-Box Binding Protein 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; C020723:citrate-binding transport protein; D019343:Citric Acid; D000105:Acetyl Coenzyme A
keywords: ATF6; ER protein acetylation; GRP78; SLC25A1; Unfolded protein response; XBP1