{"doi":"10.7554/elife.83534.sa2","title":"Author response: A concerted mechanism involving ACAT and SREBPs by which oxysterols deplete accessible cholesterol to restrict microbial infection","abstract":"Most of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins.However, as cholesterol concentration rises above the PM's sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges.The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis.This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols.Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC).We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM.This imbalance triggers the rapid internalization of accessible cholesterol from the PM, and this depletion is sustained for long periods of time through 25HC-mediated suppression of SREBPs and continued activation of ACAT.In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, and Listeria monocytogenes infection in ACAT-deficient cells and mice.We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols. Editor's evaluationThis paper provides important and fundamental insights into the mechanisms by which 25-hydroxycholesterol, which is known to be rapidly produced in macrophages and other cells during acute infections, acts to protect cells and animals from infectious processes.The authors provide compelling evidence that the cholesterol esterifying enzyme acylCoA:cholesterol acyltransferase (ACAT) that is induced by 25-hydroxycholesterol promotes depletion of an accessible pool of plasma membrane cholesterol, producing anti-microbial effects.The work will be of interest to those studying infection and cholesterol regulation of cellular processes.","journal":null,"year":2023,"id":398476,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9455,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397447,"name":"Kristen Johnson","orcid":"0000-0003-2635-7406","position":1,"is_corresponding":false},{"id":997441,"name":"Duo Ma","orcid":"0000-0002-6736-551X","position":2,"is_corresponding":false},{"id":997440,"name":"Maikke B. Ohlson","orcid":"0000-0002-1055-2269","position":3,"is_corresponding":false},{"id":997442,"name":"Lishu Zhang","orcid":"0000-0002-1742-1456","position":4,"is_corresponding":false},{"id":997443,"name":"Michelle Tran","orcid":"0000-0002-7153-0872","position":5,"is_corresponding":false},{"id":504653,"name":"Chase D. Corley","orcid":"0000-0002-5638-9620","position":6,"is_corresponding":false},{"id":274910,"name":"Michael E. Abrams","orcid":"0000-0001-5493-0965","position":7,"is_corresponding":false},{"id":228441,"name":"Jeffrey G. McDonald","orcid":"0000-0003-1570-4142","position":8,"is_corresponding":false},{"id":241087,"name":"John W. Schoggins","orcid":"0000-0002-7944-6800","position":9,"is_corresponding":false},{"id":274918,"name":"Neal M. Alto","orcid":"0000-0002-7602-3853","position":10,"is_corresponding":false},{"id":246032,"name":"Arun Radhakrishnan","orcid":"0000-0002-7266-7336","position":11,"is_corresponding":false},{"id":623588,"name":"David B. Heisler","orcid":"0000-0002-6482-4215","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:19:47.744358Z","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":[]}