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Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade.<\/jats:p>","DOI":"10.3390\/ijms25137128","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:33:53Z","timestamp":1719920033000},"page":"7128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-5000","authenticated-orcid":false,"given":"Seyed Hesamoddin","family":"Bidooki","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Institute of Analytical Sciences and Physico-Chemistry for Environment and Materials (IPREM), Universite de Pau et des Pays de l\u2019Adour, E2S UPPA, CNRS, 64 000 Pau, France"},{"name":"MANTA\u2014Marine Materials Research Group, Universite de Pau et des Pays de l\u2019Adour, E2S UPPA, 64 600 Anglet, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8442-8041","authenticated-orcid":false,"given":"Cristina","family":"Barranquero","sequence":"additional","affiliation":[{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9023-741X","authenticated-orcid":false,"given":"Javier","family":"S\u00e1nchez-Marco","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8100-5596","authenticated-orcid":false,"given":"Roberto","family":"Mart\u00ednez-Beamonte","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-7668","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Rodr\u00edguez-Yoldi","sequence":"additional","affiliation":[{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain"},{"name":"Departamento de Farmacolog\u00eda, Fisiolog\u00eda, Medicina Legal y Forense, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0108-1004","authenticated-orcid":false,"given":"Mar\u00eda A.","family":"Navarro","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1295-5010","authenticated-orcid":false,"given":"Susana C. 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