{"doi":"10.1101/2021.03.15.435490","title":"CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids","abstract":"Introductory paragraph The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis 1 . Aberrant HH signaling can cause congenital malformations, such as digit anomalies and holoprosencephaly 2 , and other diseases, including cancer 3 . Signal transduction is initiated by HH ligand binding to the Patched 1 (PTCH1) receptor on primary cilia, thereby releasing inhibition of Smoothened (SMO), a HH pathway activator 4 . Although cholesterol and several oxysterol lipids, which are enriched in the ciliary membrane, play a crucial role in HH activation 4,5 , the molecular mechanisms governing the regulation of these lipid molecules remain unresolved. Here, we identify Canopy 4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that controls membrane sterol lipid levels. Cnpy4 −/− embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway at the level of SMO in vitro , and elevates membrane levels of accessible sterol lipids such as cholesterol, an endogenous ligand involved in SMO activation 6 . Thus, our data demonstrate that CNPY4 is a negative regulator that fine-tunes the initial steps of HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223676,"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":0.9469,"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":341345,"name":"Amnon Sharir","orcid":"0000-0003-4687-5155","position":1,"is_corresponding":false},{"id":739568,"name":"Michael Paul","orcid":"0000-0001-8479-110X","position":2,"is_corresponding":false},{"id":291243,"name":"Hayarpi Torosyan","orcid":"0000-0003-1576-0195","position":3,"is_corresponding":false},{"id":655378,"name":"Christopher Agnew","orcid":"0000-0003-0934-5534","position":4,"is_corresponding":false},{"id":88538,"name":"David R. Raleigh","orcid":"0000-0001-9299-8864","position":5,"is_corresponding":false},{"id":1485,"name":"Natalia Jura","orcid":"0000-0001-5129-641X","position":6,"is_corresponding":false},{"id":237994,"name":"Ophir D. Klein","orcid":"0000-0002-6254-7082","position":7,"is_corresponding":false},{"id":108158,"name":"Megan Lo","orcid":"0000-0002-6387-8182","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-18T23:54:14.760456Z","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":[]}