{"doi":"10.1101/2021.08.05.455205","title":"Co-translational biogenesis of lipid droplet integral membrane proteins","abstract":"ABSTRACT Membrane proteins destined for lipid droplets (LDs), a major intracellular storage site for neutral lipids, are inserted into the endoplasmic reticulum (ER) and then trafficked to LDs where they reside in a hairpin loop conformation. Here, we show that LD membrane proteins can be delivered to the ER either co- or post-translationally and that their membrane-embedded region specifies pathway selection. The co-translational route for LD membrane protein biogenesis is insensitive to a small molecule inhibitor of the Sec61 translocon, Ipomoeassin F, and instead relies on the ER membrane protein complex (EMC) for membrane insertion. Strikingly, this route can also result in a transient exposure of the short N-termini of LD membrane proteins to the ER lumen, followed by topological rearrangements that enable their transmembrane segment to form a hairpin loop and N-termini to face the cytosol. Our study reveals an unexpected complexity to LD membrane protein biogenesis and identifies a role for the EMC during their co-translational insertion into the ER. SUMMARY STATEMENT Insertion of many lipid droplet membrane proteins into the endoplasmic reticulum (ER) is co-translational, mediated by the ER membrane protein complex (EMC) and involves topology reorientation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226007,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":577210,"name":"Hayden Schneider","orcid":"0000-0002-7373-3649","position":1,"is_corresponding":false},{"id":712499,"name":"Jada V. Harvey","orcid":null,"position":2,"is_corresponding":false},{"id":474728,"name":"Wei Shi","orcid":"0000-0001-5453-1753","position":3,"is_corresponding":false},{"id":474726,"name":"Stephen High","orcid":"0000-0002-4532-8152","position":4,"is_corresponding":false},{"id":711897,"name":"Paweł Leźnicki","orcid":"0000-0002-2687-107X","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:54:30.292454Z","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":[]}