{"doi":"10.3389/fimmu.2022.1079962","title":"SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure","abstract":"Alcohol abuse, reported by 1/8 th critically ill patients, is an independent risk factor for death in sepsis. Sepsis kills over 270,000 patients/year in the US. We reported that the ethanol-exposure suppresses innate-immune response, pathogen clearance, and decreases survival in sepsis-mice via sirtuin 2 (SIRT2). SIRT2 is an NAD+-dependent histone-deacetylase with anti-inflammatory properties. We hypothesized that in ethanol-exposed macrophages, SIRT2 suppresses phagocytosis and pathogen clearance by regulating glycolysis. Immune cells use glycolysis to fuel increased metabolic and energy demand of phagocytosis. Using ethanol-exposed mouse bone marrow- and human blood monocyte-derived macrophages, we found that SIRT2 mutes glycolysis via deacetylating key glycolysis regulating enzyme phosphofructokinase-platelet isoform (PFKP), at mouse lysine 394 (mK394, human: hK395). Acetylation of PFKP at mK394 (hK395) is crucial for PFKP function as a glycolysis regulating enzyme. The PFKP also facilitates phosphorylation and activation of autophagy related protein 4B (Atg4B). Atg4B activates microtubule associated protein 1 light chain-3B (LC3). LC3 is a driver of a subset of phagocytosis, the LC3-associated phagocytosis (LAP), which is crucial for segregation and enhanced clearance of pathogens, in sepsis. We found that in ethanol-exposed cells, the SIRT2-PFKP interaction leads to decreased Atg4B-phosphorylation, decreased LC3 activation, repressed phagocytosis and LAP. Genetic deficiency or pharmacological inhibition of SIRT2 reverse PFKP-deacetylation, suppressed LC3-activation and phagocytosis including LAP, in ethanol-exposed macrophages to improve bacterial clearance and survival in ethanol with sepsis mice.","journal":"Frontiers in Immunology","year":2023,"id":335031,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9479,"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":250568,"name":"Sanjoy Roychowdhury","orcid":"0000-0002-1264-6496","position":1,"is_corresponding":false},{"id":429334,"name":"Christopher Kibler","orcid":null,"position":2,"is_corresponding":false},{"id":1054956,"name":"Emily S. Cross","orcid":"0000-0002-1671-5698","position":3,"is_corresponding":false},{"id":303541,"name":"Susamma Abraham","orcid":null,"position":4,"is_corresponding":false},{"id":1064404,"name":"Annett Bellar","orcid":null,"position":5,"is_corresponding":false},{"id":250570,"name":"Laura E. Nagy","orcid":"0000-0002-0580-2809","position":6,"is_corresponding":false},{"id":302606,"name":"R.G. Scheraga","orcid":"0000-0001-5113-543X","position":7,"is_corresponding":false},{"id":383297,"name":"Vidula Vachharajani","orcid":"0000-0002-0892-7084","position":8,"is_corresponding":false},{"id":429333,"name":"Anugraha Gandhirajan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:53.742667Z","pmid":"36865524","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":[]}