{"doi":"10.1002/2211-5463.13484","title":"A systems biological analysis of the <scp>ATF4‐GADD34‐CHOP</scp> regulatory triangle upon endoplasmic reticulum stress","abstract":"<jats:p>Endoplasmic reticulum (ER) stress‐dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the unfolded protein response (UPR) is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here we investigated the ER stress‐dependent feedback loops inside one of the UPR branches by focusing on PERK‐induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behavior of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life‐or‐death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine‐tuning of the ATF4‐dependent stress response mechanism of the cell.</jats:p>","journal":"FEBS Open Bio","year":2022,"id":24261,"datarank":0.8955424163975099,"base_score":3.4657359027997265,"endowment":3.4657359027997265,"self_citation_contribution":0.519860385419959,"citation_network_contribution":0.3756820309775509,"self_endowment_contribution":0.519860385419959,"citer_contribution":0.3756820309775509,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":28,"citers_with_citation_signal":20,"citers_with_endowment":20,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":146167,"name":"Gábor Bánhegyi","orcid":null,"position":1,"is_corresponding":false},{"id":146168,"name":"Norbert Gyöngyösi","orcid":null,"position":2,"is_corresponding":false},{"id":146169,"name":"Eszter Éva Kálmán","orcid":null,"position":3,"is_corresponding":false},{"id":146170,"name":"Aladár Pettkó‐Szandtner","orcid":null,"position":4,"is_corresponding":false},{"id":146171,"name":"Krisztina Káldi","orcid":null,"position":5,"is_corresponding":false},{"id":146172,"name":"Orsolya Kapuy","orcid":"0000-0002-8484-4504","position":6,"is_corresponding":false},{"id":146166,"name":"Margita Márton","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.4657359027997265,"endowment":3.4657359027997265,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36097827","pmcid":"PMC9623533","openalex_id":"https://openalex.org/W4295500741","authors":[],"funders":[{"funder_name":"Emberi Eroforrások Minisztériuma","grant_id":"ÚNKP‐22‐4‐II‐SE‐20","title":null},{"funder_name":"European Commission","grant_id":"739593","title":"Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership with EMBL"}],"total_grants":2,"fwci":2.9106,"citation_percentile":0.91595496,"influential_citations":1,"citation_trend":[{"year":2023,"count":6},{"year":2024,"count":9},{"year":2025,"count":10},{"year":2026,"count":6}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/2211-5463.13484","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/2211-5463.13484","host_type":"GOLD"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/2211-5463.13484","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/2211-5463.13484","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/2211-5463.13484","host_type":"publisher"},{"url":"https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/2211-5463.13484","host_type":"publisher"},{"url":"https://doi.org/10.1002/2211-5463.13484","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36097827","host_type":"repository"},{"url":"https://doaj.org/article/13614439e3c84ceba43168b1ac76dbb7","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9623533","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9623533","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9623533?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1002/2211-5463.13484","host_type":""},{"url":"https://doi.org/https://doi.org/10.1002/2211-5463.13484","host_type":""}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","Autophagy in Disease and Therapy","CRISPR and Genetic Engineering","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Humans","Activating Transcription Factor 4","Endoplasmic Reticulum Stress","HEK293 Cells","Transcription Factor CHOP","Unfolded Protein Response","Protein Phosphatase 1"],"mesh_terms":["Humans","Activating Transcription Factor 4","Transcription Factor CHOP","Protein Phosphatase 1","Unfolded Protein Response","HEK293 Cells","Endoplasmic Reticulum Stress"],"keywords":["Unfolded protein response","ATF4","Endoplasmic reticulum","CHOP","Cell biology","Regulator","Autophagy","Chemistry","HEK 293 cells","Endoplasmic-reticulum-associated protein degradation","Apoptosis","Biology","Biochemistry","Gene","systems biology","endoplasmic reticulum stress","Feedback Loop","Perk Pathway","Atf4-gadd34-chop","QH3015 Molecular biology / molekuláris biológia","QH301-705.5","Activating Transcription Factor 4","HEK293 Cells","Protein Phosphatase 1","ATF4‐GADD34‐CHOP","Humans","Biology (General)","Research Articles","Transcription Factor CHOP"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Peace, Justice and strong institutions"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.26639349.v1","title":"Additional file 1 of CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26639349","title":"Additional file 1 of CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns","publisher":"figshare","resource_type":"Image"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-07T21:59:06.458102Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}