{"doi":"10.1016/j.devcel.2024.07.004","title":"Sestrin2 drives ER-phagy in response to protein misfolding","abstract":"Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs.","journal":"Developmental Cell","year":2024,"id":420292,"datarank":0.8340279101732873,"base_score":3.58351893845611,"endowment":3.58351893845611,"self_citation_contribution":0.5375278407684165,"citation_network_contribution":0.2965000694048707,"self_endowment_contribution":0.5375278407684165,"citer_contribution":0.2965000694048707,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":33,"citers_with_citation_signal":20,"citers_with_endowment":20,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE239527","GSE239525","GSE239528"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1211181,"name":"Marianna Maddaluno","orcid":"0000-0002-7117-023X","position":1,"is_corresponding":false},{"id":1211182,"name":"Rosa Ferriero","orcid":"0000-0001-5090-6087","position":2,"is_corresponding":false},{"id":666293,"name":"Roberta Besio","orcid":"0000-0003-1430-2934","position":3,"is_corresponding":false},{"id":1026716,"name":"Laura Cinque","orcid":"0000-0002-8497-3939","position":4,"is_corresponding":false},{"id":782495,"name":"Pei Jin Lim","orcid":"0000-0003-4201-1210","position":5,"is_corresponding":false},{"id":841641,"name":"Alessandro Palma","orcid":"0000-0003-1300-5479","position":6,"is_corresponding":false},{"id":628610,"name":"Rossella De Cegli","orcid":"0000-0002-8526-8692","position":7,"is_corresponding":false},{"id":1211688,"name":"Salvatore Gagliotta","orcid":null,"position":8,"is_corresponding":false},{"id":1211689,"name":"Sandro Montefusco","orcid":null,"position":9,"is_corresponding":false},{"id":1211183,"name":"Maria Iavazzo","orcid":"0000-0003-3627-9587","position":10,"is_corresponding":false},{"id":230660,"name":"Marianne Rohrbach","orcid":"0000-0002-4013-6012","position":11,"is_corresponding":false},{"id":782499,"name":"Cecilia Giunta","orcid":"0000-0002-9313-8257","position":12,"is_corresponding":false},{"id":356338,"name":"Elena Polishchuk","orcid":"0000-0002-6053-1060","position":13,"is_corresponding":false},{"id":1211690,"name":"Diego Louis Medina","orcid":null,"position":14,"is_corresponding":false},{"id":994387,"name":"Diego di Bernardo","orcid":"0000-0002-1911-7407","position":15,"is_corresponding":false},{"id":365010,"name":"Antonella Forlino","orcid":"0000-0002-6385-1182","position":16,"is_corresponding":false},{"id":1211184,"name":"Pasquale Piccolo","orcid":"0000-0002-8614-2581","position":17,"is_corresponding":false},{"id":323914,"name":"Carmine Settembre","orcid":"0000-0002-5829-8589","position":18,"is_corresponding":false},{"id":1211180,"name":"Chiara De Leonibus","orcid":"0000-0003-4440-3402","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:57:25.777459Z","pmid":"39094564","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":[]}