{"doi":"10.1101/2020.11.06.372292","title":"βPix sequesters IDOL and prevents LDL receptor degradation through a β <sub>2</sub> AR-regulated signaling pathway in Alport Syndrome","abstract":"ABSTRACT Alport syndrome (AS) is a rare disease of the glomerular basement membrane type IV collagen causing progressive renal failure. We reported increased accumulation of low-density lipoprotein (LDL) receptor (LDLR) and subsequent LDL cholesterol (LDL-C) uptake in renal tubular epithelial cells (TEC) in Alport mice, but the mechanisms regulating LDLR stability and function remain unknown. Here, we show that a selective β 2 -Adrenoceptor (β 2 AR) agonist, salbutamol, decreased LDLR levels and LDL-C uptake in Alport kidneys accompanied with reduced albuminuria and improved cardiac systolic and diastolic function. Similarly, salbutamol decreased LDL-C uptake in HK2 and HEK293 human renal epithelial cell lines, in smooth muscle cells from an X-linked hereditary nephropathy dog model (a large animal model of AS), and in TECs differentiated from AS patient-derived iPSCs. We show that the Rac1/Cdc42 guanine nucleotide exchange factor β1Pix blocked β 2 AR-induced LDLR degradation and, hence, increased LDL-C uptake. β1Pix also abrogated ubiquitination and degradation of LDLR induced by the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase that promotes lysosomal LDLR ubiquitination and degradation. We identify a multimolecular complex comprised of βPix, IDOL, and LDLR and demonstrate that βPix counteracts β 2 AR-mediated LDLR degradation by sequestering IDOL. Our findings show βPix acts as a significant post-transcriptional regulator of IDOL-mediated LDLR degradation and identify β 2 AR activation as a potential treatment for Alport pathology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131436,"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":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397418,"name":"Keyvan Yousefi","orcid":"0000-0002-6115-1529","position":1,"is_corresponding":false},{"id":443281,"name":"José Manuel Cóndor Capcha","orcid":"0000-0002-8005-6244","position":2,"is_corresponding":false},{"id":443280,"name":"Camila Iansen Irion","orcid":"0000-0001-8143-043X","position":3,"is_corresponding":false},{"id":586226,"name":"Guerline Lambert","orcid":null,"position":4,"is_corresponding":false},{"id":430278,"name":"Serene A. Shehadeh","orcid":"0000-0001-8084-7516","position":5,"is_corresponding":false},{"id":444423,"name":"Julian C. Dunkley","orcid":null,"position":6,"is_corresponding":false},{"id":585428,"name":"Yee‐Shuan Lee","orcid":"0000-0003-0250-6542","position":7,"is_corresponding":false},{"id":408636,"name":"Aisha Khan","orcid":"0000-0001-7409-9208","position":8,"is_corresponding":false},{"id":280305,"name":"Melina Ramic","orcid":null,"position":9,"is_corresponding":false},{"id":280304,"name":"Nadja S. Andrade","orcid":null,"position":10,"is_corresponding":false},{"id":21545,"name":"Zane Zeier","orcid":"0000-0003-0623-8610","position":11,"is_corresponding":false},{"id":392129,"name":"Derek M. Dykxhoorn","orcid":"0000-0002-4998-9943","position":12,"is_corresponding":false},{"id":585429,"name":"Chryso Katsoufis","orcid":"0000-0002-8872-1165","position":13,"is_corresponding":false},{"id":468992,"name":"Michael Freundlich","orcid":"0000-0001-6629-3158","position":14,"is_corresponding":false},{"id":88819,"name":"Joshua M. Hare","orcid":"0000-0002-7751-5032","position":15,"is_corresponding":false},{"id":432920,"name":"Mary B. Nabity","orcid":"0000-0001-6787-822X","position":16,"is_corresponding":false},{"id":585430,"name":"Carolina Rivera","orcid":"0000-0003-0309-3591","position":17,"is_corresponding":false},{"id":424791,"name":"Anastasios Lymperopoulos","orcid":"0000-0001-9817-6319","position":18,"is_corresponding":false},{"id":397422,"name":"Lina A. Shehadeh","orcid":"0000-0003-2095-9326","position":19,"is_corresponding":false},{"id":586225,"name":"Ahmed Chahdi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","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":[]}