McFadden Michael J, Reynolds Mack B, Michmerhuizen Britton C, Ólafsson Einar B, Marshall Sofia M, Davis Faith Anderson, Schultz Tracey L, Iwawaki Takao, Sexton Jonathan Z, O'Riordan Mary X D, O'Meara Teresa R
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan.
Cell Rep. 2025 May 27;44(5):115694. doi: 10.1016/j.celrep.2025.115694. Epub 2025 May 9.
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.
哺乳动物内质网（ER）应激传感器肌醇需求酶1α（IRE1α）对细胞稳态至关重要，在包括先天免疫和杀菌活性在内的感染反应中发挥关键作用。虽然已知IRE1α通过IRE1α-XBP1S轴发挥作用，但其不依赖XBP1S的作用了解较少，其在真菌感染过程中的功能仍在不断显现。我们证明白色念珠菌通过C型凝集素受体信号通路激活巨噬细胞IRE1α，而不依赖于蛋白质错误折叠，提示非经典激活。IRE1α通过促进吞噬体成熟增强巨噬细胞的杀真菌活性，这对于抑制白色念珠菌菌丝至关重要。IRE1α促进吞噬后早期吞噬体钙通量，这是吞噬溶酶体融合所必需的。在缺乏IRE1α核糖核酸内切酶结构域的巨噬细胞中，有缺陷的钙通量与较少的内质网-早期内体接触位点相关，提示IRE1α促进膜接触位点具有稳态作用。总体而言，我们的研究结果阐明了感染过程中非经典的IRE1α激活以及IRE1α在支持细胞器接触位点以抵御快速生长的微生物方面的功能。
