{"doi":"10.1016/j.celrep.2025.115694","title":"IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity","abstract":"The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.","journal":"Cell Reports","year":2025,"id":516656,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"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":692228,"name":"Mack B. Reynolds","orcid":"0000-0002-8445-3749","position":1,"is_corresponding":false},{"id":996344,"name":"Britton C Michmerhuizen","orcid":"0009-0000-5997-9581","position":2,"is_corresponding":false},{"id":660679,"name":"Einar B. Ólafsson","orcid":"0000-0002-3388-061X","position":3,"is_corresponding":false},{"id":1232924,"name":"Sofia A. Marshall","orcid":null,"position":4,"is_corresponding":false},{"id":1382462,"name":"Faith Anderson Davis","orcid":null,"position":5,"is_corresponding":false},{"id":580379,"name":"Tracey L. Schultz","orcid":"0009-0008-3133-8756","position":6,"is_corresponding":false},{"id":270666,"name":"Takao Iwawaki","orcid":"0000-0001-8753-1979","position":7,"is_corresponding":false},{"id":288649,"name":"Jonathan Z. Sexton","orcid":"0000-0002-9244-5888","position":8,"is_corresponding":false},{"id":1240135,"name":"Mary X O'Riordan","orcid":null,"position":9,"is_corresponding":false},{"id":520949,"name":"Teresa R. O’Meara","orcid":"0000-0002-8901-0154","position":10,"is_corresponding":false},{"id":326143,"name":"Michael J. McFadden","orcid":"0000-0003-0303-6968","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40349346","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":[]}