{"doi":"10.1101/2023.10.16.562572","title":"TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade","abstract":"ABSTRACT Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy that plays a key role in the regulation of cellular clearance pathways. TFEB is regulated via a complex array of post-translational modifications (PTMs), but the exact molecular mechanism that regulates TFEB stability has remained elusive. Here, we show that TFEB levels are critically regulated by a defined phosphorylation-ubiquitination cascade. A human kinome screen identifies IKK (inhibitor of κB kinase) as a TFEB modifier, and a combination of phosphorylation assays, mass spectrometry analyses, and site-specific mutagenesis unveils a previously unrecognized TFEB phospho-degron ( 423 SPFPSLS 429 ) as the target of IKK. We show that IKK-mediated phosphorylation of TFEB triggers ubiquitination of adjacent lysine residues (K430 and K431) by the E3 ligase β-TrCP2 (β-Transducin repeat-containing protein 2), thereby tagging TFEB for degradation. Modified TFEB constructs that abolish these PTMs show much increased stability and expression levels but remain equally sensitive to autophagy- or stress- related stimuli while maintaining the capability to promote the expression of TFEB target genes and the clearance of Alzheimer’s associated tau in a cellular model of disease. Our results therefore uncover an IKK/β-TrCP2 phosphorylation-ubiquitination cascade as a major mechanism that governs TFEB stability independently of other TFEB regulators.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401245,"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":0.9597,"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":311579,"name":"Jai Prakash Sharma","orcid":"0000-0003-4147-1637","position":1,"is_corresponding":false},{"id":1107548,"name":"Meggie N. Young","orcid":"0000-0003-2684-7317","position":2,"is_corresponding":false},{"id":1021563,"name":"Wen Xiong","orcid":"0000-0002-2825-2061","position":3,"is_corresponding":false},{"id":1177911,"name":"Ali Jazayeri","orcid":"0000-0002-6212-4442","position":4,"is_corresponding":false},{"id":985538,"name":"Karl F. Poncha","orcid":"0000-0001-5750-227X","position":5,"is_corresponding":false},{"id":227338,"name":"Ma. Xenia G. Ilagan","orcid":"0000-0003-2888-4859","position":6,"is_corresponding":false},{"id":70805,"name":"Qing Wang","orcid":"0009-0003-7328-8762","position":7,"is_corresponding":false},{"id":110462,"name":"Hui Zheng","orcid":"0000-0002-5427-3798","position":8,"is_corresponding":false},{"id":267564,"name":"Nicolas L. Young","orcid":"0000-0002-3323-2815","position":9,"is_corresponding":false},{"id":311585,"name":"Marco Sardiello","orcid":"0000-0001-6484-0250","position":10,"is_corresponding":false},{"id":1177910,"name":"Yan Xiong","orcid":"0000-0002-9268-3907","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:20:08.195423Z","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":[]}