{"doi":"10.64898/2025.12.22.695975","title":"Molecular insights into Profilin1-dependent regulation of cellular phosphatidylinositol-(4,5)-bisphosphate","abstract":"ABSTRACT Phosphatidylinositol (4,5)-bisphosphate (PIP 2 ), the most abundant cellular poly-phosphoinositide (PPI) class of phospholipid, is a central plasma membrane (PM)-associated signaling hub that controls many cellular processes. In this study, we demonstrate that either deletion of the gene encoding actin-binding protein profilin1 (Pfn1) or disruption of Pfn1-actin interaction leads to downregulation of PM PIP 2 content in cells. This is also phenocopied when F-actin is depolymerized implying that Pfn1-dependent PIP 2 alteration is related to its actin-regulatory function. Phospholipase C (PLC) activity is critical for Pfn1-deficient cells to exhibit the PIP 2 -related phenotype. These findings, taken together with biochemical signatures of elevated PIP 2 hydrolysis (higher baseline PM diacylglycerol-to PIP 2 ratio and protein kinase C activity) exhibited by Pfn1-deficient cells, imply that PLC-mediated PIP 2 hydrolysis plays a role in Pfn1-dependent regulation of PM PIP 2 . Furthermore, we unexpectedly found that Pfn1 loss leads to dramatic alterations in several other important forms of lipids, revealing a previously unrecognized role of Pfn1 as a broad regulator of cellular lipid environment that extends beyond PPI control. In conclusion, our study establishes Pfn1 as an important regulator of cellular lipid homeostasis. SUMMARY STATEMENT This study uncovers a mechanism of how functional loss of Profilin1, a key regulator of actin cytoskeleton, can trigger downregulation of plasma membrane content of PIP 2 , an important class of phospholipid, in cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":586834,"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":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1501919,"name":"Michael J. Chirumbolo","orcid":null,"position":1,"is_corresponding":false},{"id":916773,"name":"Ian Eder","orcid":"0000-0001-7111-9752","position":2,"is_corresponding":false},{"id":1501920,"name":"Jia-Jun Liu","orcid":null,"position":3,"is_corresponding":false},{"id":279404,"name":"Silvia Liu","orcid":"0000-0002-1840-9520","position":4,"is_corresponding":false},{"id":402780,"name":"David Gau","orcid":"0000-0002-3079-3692","position":5,"is_corresponding":false},{"id":294092,"name":"Yubo Tang","orcid":"0000-0003-2568-8940","position":6,"is_corresponding":false},{"id":473932,"name":"Klemens Rottner","orcid":"0000-0003-4244-4198","position":7,"is_corresponding":false},{"id":329210,"name":"Jianhua Luo","orcid":"0000-0002-3189-4225","position":8,"is_corresponding":false},{"id":245412,"name":"Gerald Hammond","orcid":"0000-0002-6660-3272","position":9,"is_corresponding":false},{"id":402783,"name":"Partha Roy","orcid":"0000-0002-4946-8531","position":10,"is_corresponding":false},{"id":1099763,"name":"Andrew Orenberg","orcid":"0000-0002-8632-7519","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:32.191237Z","pmid":"41509374","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":[]}