{"doi":"10.1101/2023.05.08.539894","title":"Lipid Transfer Proteins and PI4KIIα Initiate Nuclear p53-Phosphoinositide Signaling","abstract":"Summary Phosphoinositide (PIP n ) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP n complexes (p53-PIP n signalosome) that activate Akt by a PI3,4,5P 3 -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP n s that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP n synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIP n complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze the formation of p53-PI4P. p53-PI4P is then sequentially phosphorylated to synthesize p53-PIP n complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this way, PITPα/β and PI4KIIα bind p53 and collaborate to initiate p53-PIP n signaling by mechanisms that require PI transfer by PITPα/β and the catalytic activity of PI4KIIα. Moreover, the identification of these critical upstream regulators of p53-PIP n signaling point to PITPα/β and PI4KIIα as potential therapeutic targets in this pathway for diseases like cancer. In Breif Phosphatidylinositol transfer proteins and a PI 4-kinase initiate nuclear p53-PIP n signaling in membrane-free regions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":389993,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"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":1052983,"name":"Mo Chen","orcid":"0000-0002-3274-5889","position":1,"is_corresponding":false},{"id":334119,"name":"Tianmu Wen","orcid":"0009-0002-2495-5488","position":2,"is_corresponding":false},{"id":1161213,"name":"Poorwa Awasthi","orcid":"0000-0001-9594-5661","position":3,"is_corresponding":false},{"id":1161828,"name":"Colin Sterling","orcid":null,"position":4,"is_corresponding":false},{"id":1161829,"name":"Dhruv Brahmbhatt","orcid":null,"position":5,"is_corresponding":false},{"id":285809,"name":"Vincent L. Cryns","orcid":"0000-0003-0355-2268","position":6,"is_corresponding":false},{"id":334121,"name":"Richard A. Anderson","orcid":"0000-0001-6265-8359","position":7,"is_corresponding":false},{"id":1052982,"name":"Noah D. Carrillo","orcid":"0000-0002-1914-1095","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T01:18:32.854511Z","pmid":"37214930","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":[]}