{"doi":"10.1101/2025.10.02.679826","title":"Atg16l1 promotes lung transplant tolerance by regulating glycolysis in macrophages","abstract":"Abstract Lung transplant survival is limited by the development of chronic lung allograft dysfunction (CLAD), a type of graft rejection that lacks effective treatments. Autophagy plays a crucial role in maintaining cellular homeostasis. In a single-nucleotide polymorphism screen, we found that lung recipients with two copies of a common hypofunctional genetic variant of autophagy-related 16-like 1 rs2241880 ( ATG16L1 T300A/T300A ), known to deplete this protein from macrophages, were more likely to develop early CLAD. To understand this, we used a mouse orthotopic lung transplant model. Recipients encoding myeloid cell-specific deletion of Atg16l1 ( Atg16l1 Δ/Δ ) or who harbor an engineered orthologous mutation ( Atg16l1 T316A/T316A ) showed similar susceptibility to CLAD. Transcript profiling and mitochondrial tracking studies indicated that increased mitochondrial damage and decreased autophagic removal of mitochondria in Atg16l1-deficient macrophages were associated with heightened activation of the hypoxia-inducible factor 1α (Hif1α) pathway and accumulation of glycolytic transcripts. Metabolic analysis revealed reduced oxidative phosphorylation, increased glycolytic activity, and higher IL-1β expression in Atg16l1-deficient macrophages. Notably, the development of CLAD in Atg16l1 Δ/Δ lung recipients could be significantly prevented by additionally deleting Hif1α in myeloid cells or by treating with the glycolysis inhibitor 2-deoxyglucose. Our results show how a common autophagy-related genetic variant disrupts macrophage metabolism and impairs lung transplant tolerance, pointing toward potential therapeutic strategies to combat CLAD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":576872,"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":0.9539,"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":497620,"name":"Fuyi Liao","orcid":"0000-0001-7733-084X","position":1,"is_corresponding":false},{"id":497621,"name":"Dequan Zhou","orcid":"0000-0002-2662-2882","position":2,"is_corresponding":false},{"id":426545,"name":"Catherine Chen","orcid":"0000-0001-6108-2044","position":3,"is_corresponding":false},{"id":1368138,"name":"Zhiyi Liu","orcid":"0009-0008-9452-0547","position":4,"is_corresponding":false},{"id":551338,"name":"Ji Hong Zhu","orcid":null,"position":5,"is_corresponding":false},{"id":897255,"name":"Cory T. 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