IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity
Summary: 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, it...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004656 |
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| author | Michael J. McFadden Mack B. Reynolds Britton C. Michmerhuizen Einar B. Ólafsson Sofia M. Marshall Faith Anderson Davis Tracey L. Schultz Takao Iwawaki Jonathan Z. Sexton Mary X.D. O’Riordan Teresa R. O’Meara |
| author_facet | Michael J. McFadden Mack B. Reynolds Britton C. Michmerhuizen Einar B. Ólafsson Sofia M. Marshall Faith Anderson Davis Tracey L. Schultz Takao Iwawaki Jonathan Z. Sexton Mary X.D. O’Riordan Teresa R. O’Meara |
| author_sort | Michael J. McFadden |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-90446844aff941cb8460bf7e970ef3cf |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-90446844aff941cb8460bf7e970ef3cf2025-08-20T03:09:16ZengElsevierCell Reports2211-12472025-05-0144511569410.1016/j.celrep.2025.115694IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activityMichael J. McFadden0Mack B. Reynolds1Britton C. Michmerhuizen2Einar B. Ólafsson3Sofia M. Marshall4Faith Anderson Davis5Tracey L. Schultz6Takao Iwawaki7Jonathan Z. Sexton8Mary X.D. O’Riordan9Teresa R. O’Meara10Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, JapanDepartment of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding authorDepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725004656CP: ImmunologyCP: Microbiology |
| spellingShingle | Michael J. McFadden Mack B. Reynolds Britton C. Michmerhuizen Einar B. Ólafsson Sofia M. Marshall Faith Anderson Davis Tracey L. Schultz Takao Iwawaki Jonathan Z. Sexton Mary X.D. O’Riordan Teresa R. O’Meara IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity Cell Reports CP: Immunology CP: Microbiology |
| title | IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| title_full | IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| title_fullStr | IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| title_full_unstemmed | IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| title_short | IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| title_sort | ire1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity |
| topic | CP: Immunology CP: Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004656 |
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